Isolated human transporter proteins, nucleic acid molecules encoding human transporter proteins, and uses thereof

ABSTRACT

The present invention provides amino, acid sequences of peptides that are encoded by genes within the human genome, the transporter peptides of the present invention. The present invention specifically provides isolated peptide and nucleic, acid molecules, methods of identifying orthologs and paralogs of the transporter peptides, and methods of identifying modulators of the transporter peptides.

FIELD OF THE INVENTION

[0001] The present invention is in the field of transporter proteins that are related to the mitochondrial solute carrier subfamily, recombinant DNA molecules, and protein production. The present invention specifically provides novel peptides and proteins that effect ligand transport and nucleic acid molecules encoding such peptide and protein molecules, all of which are useful in the development of human therapeutics and diagnostic compositions and methods.

BACKGROUND OF THE INVENTION

[0002] Transporters

[0003] Transporter proteins regulate many different functions of a cell, including cell proliferation, differentiation, and signaling processes, by regulating the flow of molecules such as ions and macromolecules, into and out of cells. Transporters are found in the plasma membranes of virtually every cell in eukaryotic organisms. Transporters mediate a variety of cellular functions including regulation of membrane potentials and absorption and secretion of molecules and ion across cell membranes. When present in intracellular membranes of the Golgi apparatus and endocytic vesicles, transporters, such as chloride channels, also regulate organelle pH. For a review, see Greger, R. (1988) Annu. Rev. Physiol. 50:111-122.

[0004] Transporters are generally classified by structure and the type of mode of action. In addition, transporters are sometimes classified by the molecule type that is transported, for example, sugar transporters, chlorine channels, potassium channels, etc. There may be many classes of channels for transporting a single type of molecule (a detailed review of channel types can be found at Alexander, S. P. H. and J. A. Peters: Receptor and transporter nomenclature supplement. Trends Pharmacol. Sci., Elsevier, pp. 65-68 (1997) and http://www-biology.ucsd.edu/msaier/transport/titlepage2.html.

[0005] The following general classification scheme is known in the art and is followed in the present discoveries.

[0006] Channel-type transporters. Transmembrane channel proteins of this class are ubiquitously found in the membranes of all types of organisms from bacteria to higher eukaryotes. Transport systems of this type catalyze facilitated diffusion (by an energy-independent process) by passage through a transmembrane aqueous pore or channel without evidence for a carrier-mediated mechanism. These channel proteins usually consist largely of a-helical spanners, although b-strands may also be present and may even comprise the channel. However, outer membrane porin-type channel proteins are excluded from this class and are instead included in class 9.

[0007] Carrier-type transporters. Transport systems are included in this class if they utilize a carrier-mediated process to catalyze uniport (a single species is transported by facilitated diffusion), antiport (two or more species are transported in opposite directions in a tightly coupled process, not coupled to, a direct form of energy other than cheimiosmotic energy) and/or symport (two or more species are transported together in the same direction in a tightly coupled process, not coupled to a direct form of energy other than chemiosmotic energy).

[0008] Pyrophosphate bond hydrolysis-driven active transporters. Transport systems are included in this class if they hydrolyze pyrophosphate or the terminal pyrophosphate bond in ATP or another nucleoside triphosphate to drive the active uptake and/or extrusion of a solute or solutes. The transport protein may or may not be transiently phosphorylated, but the substrate is not phosphorylated.

[0009] PEP-dependent, phosphoryl transfer-driven group translocators. Transport systems of the bacterial phosphoenolpyruvate:sugar phosphotransferase system are included in this class. The product of the reaction, derived from extracellular sugar, is a cytoplasmic sugar-phosphate.

[0010] Decarboxylation-driven active transporters. Transport systems that drive solute (e.g., ion) uptake or extrusion by decarboxylation of a cytoplasmic substrate are included in this class.

[0011] Oxidoreduction-driven active transporters. Transport systems that drive transport of a solute (e.g., an ion) energized by the flow of electrons from a reduced substrate to an oxidized substrate are included in this class.

[0012] Light-driven-active transporters. Transport systems that utilize light energy to drive transport of a solute (e.g., an ion) are included in this class.

[0013] Mechanically-driven active transporters. Transport systems are included in this class if they drive movement of a cell or organelle by allowing the flow of ions (or other solutes) through the membrane down their electrochemical gradients.

[0014] Outer-membrane porins (of b-structure). These proteins form transmembrane pores or channels that usually allow the energy independent passage of solutes across a membrane. The transmembrane portions of these proteins consist exclusively of b-strands that form a b-barrel. These porin-type proteins are found in the outer membranes of Gram-negative bacteria, mitochondria and eukaryotic plastids.

[0015] Methyltransferase-driven active transporters. A single characterized protein currently falls into this category, the Na+-transporting methyltetrahydromethanopterin:coenzyme M methyltransferase.

[0016] Non-ribosome-synthesized channel-forming peptides or peptide-like molecules. These molecules usually chains of L- and D-amino acids as well as other small molecular building blocks such as lactate, form oligomeric transmembrane ion channels. Voltage may induce channel formation by promoting assembly of the transmembrane channel. These peptides are often made by bacteria and fungi as agents of biological warfare.

[0017] Non-Proteinaceous Transport Complexes. Ion conducting substances in biological membranes that do not consist of or, are not derived from proteins or peptides fall into this category.

[0018] Functionally characterized transporters for which sequence data are lacking. Transporters of particular physiological significance will be included in this category even though a family assignment cannot be made.

[0019] Putative transporters in which no family member is an established transporter. Putative transport protein families are grouped under this number and will either be classified elsewhere when the transport function of a member becomes established, or will be eliminated from the TC classification system if the proposed transport function is disproven. These families include a member or members for which a transport function has been suggested, but evidence for such a function is not yet compelling.

[0020] Auxiliary transport proteins. Proteins that in some way facilitate transport across one or more biological membranes but do not themselves participate directly in transport are included in this class. These proteins always function in conjunction with one or more transport proteins. They may provide a function connected with energy coupling to transport, play a structural role in complex formation or serve a regulatory function.

[0021] Transporters of unknown classification. Transport protein families of unknown classification are grouped under this number and will be classified elsewhere when the transport process and energy coupling mechanism are characterized. These families include at least one member for which a transport function has been established, but either the mode of transport or the energy coupling mechanism is not known.

[0022] Ion Channels

[0023] An important type of transporter is the ion channel. Ion channels regulate many different cell proliferation, differentiation, and signaling processes by regulating the flow of ions into and out of cells. Ion channels are found in the plasma membranes of virtually every cell in eukaryotic organisms. Ion channels mediate a variety of cellular functions including regulation of membrane potentials and absorption and secretion of ion across epithelial membranes. When present in intracellular membranes of the Golgi apparatus and endocytic vesicles, ion channels, such as chloride channels, also regulate organelle pH. For a review, see Greger, R. (1988) Annu. Rev. Physiol. 50:111-122.

[0024] Ion channels are generally classified by structure and the type of mode of action. For example, extracellular ligand gated channels (ELGs) are comprised of five polypeptide subunits, with each subunit having 4 membrane spanning domains, and are activated by the binding of an extracellular ligand to the channel. In addition, channels are sometimes classified by the ion type that is transported, for example, chlorine channels, potassium channels, etc. There may be many classes of channels for transporting a single type of ion (a detailed review of channel types can be found at Alexander, S. P. H. and J. A. Peters (1997). Receptor and ion channel nomenclature supplement. Trends Pharmacol. Sci., Elsevier, pp. 65-68 and http://www-biology.ucsd.edu/msaier/transport/toc.html.

[0025] There are many types of ion channels based on structure. For example, many ion channels fall within one of the following groups: extracellular ligand-gated channels (ELG), intracellular ligand-gated channels (ILG), inward rectifying channels (INR), intercellular (gap junction) channels, and voltage gated channels (VIC). There are additionally recognized other channel families based on ion-type transported, cellular location and drug sensitivity. Detailed information on each of these, their activity, ligand type, ion type, disease association, drugability, and other information pertinent to the present invention, is well known in the art.

[0026] Extracellular ligand-gated channels, ELGs, are generally comprised of five polypeptide subunits, Unwin, N. (1993), Cell 72: 31-41; Unwin, N. (1995), Nature 373: 37-43; Hucho, F., et al., (1996) J. Neurochem. 66: 1781-1792; Hucho, F., et al., (1996) Eur. J. Biochem., 239: 539-557; Alexander, S. P. H. and J. A. Peters (1997), Trends, Pharmacol. Sci., Elsevier, pp. 4-6; 36-40; 42-44; and Xue, H. ((1998) J. Mol. Evol. 47: 323-333. Each subunit has 4 membrane spanning regions: this serves as a means of identifying other members of the ELG family of proteins. ELG bind a ligand and in response modulate the flow of ions. Examples of ELG include most members of the neurotransmitter-receptor family of proteins, e.g., GABAI receptors. Other members of this family of ion channels include glycine receptors, ryandyne receptors, and ligand gated calcium channels.

[0027] The Voltage-Gated Ion Channel (VIC) Superfamily

[0028] Proteins of the VIC family are ion-selective channel proteins found in a wide range of bacteria, archaea and eukaryotes Hille, B. (1992), Chapter 9: Structure of channel proteins; Chapter 20: Evolution and diversity. In: Ionic Channels of Excitable Membranes, 2nd Ed., Sinaur Assoc. Inc., Pubs., Sunderland, Mass.; Sigworth, F. J. (1993), Quart. Rev. Biophys. 27: 1-40; Salkoff, L. and T. Jegla (1995), Neuron 15: 489-492; Alexander, S. P. H. et al., (1997), Trends Pharmacol. Sci., Elsevier, pp. 76-84; Jan, L. Y. et al., (1997), Annu. Rev. Neurosci. 20: 91-123; Doyle, D. A, et al., (1998) Science 280: 69-77; Terlau, H. and W. Stühmer (1998), Naturwissenschaften 85: 437-444. They are often homo- or heterooligomeric structures with several dissimilar subunits (e.g., a1-a2-d-b Ca²⁺ channels, ab₁b₂ Na⁺ channels or (a)₄-b K⁺ channels), but the channel and the primary receptor is usually associated with the a (or a1) subunit. Functionally characterized members are specific for K⁺, Na⁺ or Ca²⁺. The K⁺ channels usually consist of homotetrameric structures with each a-subunit possessing six transmambrane spanners (TMSs). The a1 and a subunits of the Ca²⁺ and Na⁺ channels, respectively, are about four times as large and possess 4 units, each with 6 TMSs separated by a hydrophilic loop, for a total of 24 TMSs. These large channel proteins form heterotetra-unit structures equivalent to the homotetrameric structures of most K⁺ channels. All four units of the Ca²⁺ and Na⁺ channels are homologous to the single unit in the homotetrameric K⁺ channels. Ion flux via the eukaryotic channels is generally controlled by the transmembrane electrical potential (hence the designation, voltage-sensitive) although some are controlled by ligand or receptor binding.

[0029] Several putative K⁺-selective channel proteins of the VIC family have been identified in prokaryotes. The structure, of one of them, the KcsA K⁺ channel of Streptomyces lividans, has been solved to 3.2 Å resolution. The protein possesses four identical subunits, each with two transmembrane helices, arranged in the shape of an inverted teepee or cone. The cone cradles the “selectivity filter” P domain in its outer end. The narrow selectivity filter is only 12 Å long, whereas the remainder of the channel is wider and lined with hydrophobic residues. A large water-filled cavity and helix dipoles stabilize K⁺ in the pore. The selectivity filter has two bound K⁺ ions about 7.5 Å apart from each other. Ion conduction is proposed to result from a balance of electrostatic attractive and repulsive forces.

[0030] In eukaryotes, each VIC family channel type has several subtypes based on pharmacological and electrophysiological data. Thus, there are five types of Ca²⁺ channels (L, N, P, Q and T). There are at least ten types of K⁺ channels, each responding in different ways to different stimuli: voltage-sensitive [Ka, Kv, Kvr, Kvs and Ksr], Ca²+ sensitive [BK_(Ca), IK_(Ca) and SK_(Ca)] and receptor-coupled [K_(M) and K_(ACh)]. There are at least six types of Na⁺ channels (I, II, III, μ1, H1 and PN3). Tetrameric channels from both prokaryotic and eukaryotic organisms are known in which each a-subunit possesses 2 TMSs rather than 6, and these two TMSs are homologous to TMSs 5 and 6 of the six TMS unit found in the voltage-sensitive channel proteins. KcsA of S. lividans is an example of such a 2 TMS channel protein. These channels may include the K_(Na) (Na⁺-activated) and K_(vol) (cell volume-sensitive) K⁺ channels, as well as distantly related channels such as the Tok1 K⁺ channel of yeast, the TWIK-1 inward rectifier K⁺ channel of the mouse and the TREK-1 K⁺ channel of the mouse. Because of insufficient sequence similarity with proteins of the VIC family, inward rectifier K⁺. IRK channels (ATP-regulated; G-protein-activated) which possess a P domain and two flanking TMSs are placed in a distinct family. However, substantial sequence similarity in the P region suggests that they are homologous. The b, g and d subunits of VIC family members, when present, frequently play regulatory roles in channel activation/deactivation.

[0031] The Epithelial Na⁺ Channel (ENaC) Family

[0032] The ENaC family consists of over twenty-four sequenced proteins (Canessa, C. M., et al., (1994), Nature 367: 463-467, Le, T. and M. I. Saier, Jr. (1996), Mol. Membr. Biol. 13: 149-157; Garty, H. and L. G. Palmer (1997), Physiol. Rev. 77: 359-396; Waldmann, R., et al., (1997), Nature 386:173-177; Darboux, I., et al.,(1998), J. Biol. Chem. 273: 9424-9429; Firsov, D., et al., (1998), EMBO J. 17: 344-352; Horisberger, J.-D. (1998). Curr. Opin. Struc. Biol. 10: 443-449). All are from animals with no recognizable homologues in other eukaryotes or bacteria. The vertebrate ENaC, proteins from epithelial cells cluster tightly together on the phylogenetic tree: voltage-insensitive ENaC homologues are also found in the brain. Eleven sequenced C. elegans proteins, including the degenerins, are distantly related to the vertebrate proteins as well as to each other. At least some of these proteins form part of a mechano-transducing complex for touch sensitivity. The homologous Helix aspersa (FMRF-amide)-activated Na⁺ channel is the first peptide neurotransmitter-gated ionotropic receptor to be sequenced.

[0033] Protein members of this family all exhibit the same apparent topology, each with N- and C-termini on the inside of the cell, two amphipathic transmembrane spanning segments, and a large extracellular loop. The extracellular domains contain numerous highly conserved cysteine residues. They are proposed to serve a receptor function.

[0034] Mammalian ENaC, is important for the maintenance of Na⁺ balance and the regulation of blood pressure. Three homologous ENaC subunits, alpha, beta, and gamma, have been shown to assemble to form the highly Na⁺-selective channel. The stoichiometry of the three subunits is alpha₂, beta1, gammal in a heterotetrameric architecture.

[0035] The Glutamate-Gated Ion Channel (GIC) Family of Neurotransmitter Receptors

[0036] Members of the GIC family are heteropentameric complexes in which each of the subunits is of 800-1000 amino acyl residues in length (Nakanishi, N., et al, (1990), Neuron 5: 569-581; Unwin, N. (1993), Cell 72: 31-41; Alexander, S. P. H. and J. A. Peters (1997) Trends Pharmacol. Sci., Elsevier, pp. 36-40). These subunits may span the membrane three or five times as putative a-helices with the N-termini (the glutamate-binding domains) localized extracellularly and the C-termini localized cytoplasmically. They may be distantly related to the ligand-gated ion channels, and if so, they may possess substantial b-structure in their transmembrane regions. However, homology between these two families cannot be established on the basis of sequence comparisons alone. The subunits fall into six subfamilies: a, b, g, d, e and z.

[0037] The GIC channels are divided into three types: (1) a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-, (2) kainate and (3) N-methyl-D-aspartate (NMDA)-selective glutamate receptors. Subunits of the AMPA and kainate classes exhibit 35-40% identity with each other while subunits of the NMDA receptors exhibit 22-24% identity with the former subunits. They possess large N-terminal, extracellular glutamate-binding domains that are homologous to the periplasmic glutamine and glutamate receptors of ABC-type uptake permeases of Gram-negative bacteria. All known members of the GIC family are from animals. The different channel (receptor) types exhibit distinct ion selectivities and conductance properties. The NMDA-selective large conductance channels are highly permeable to monovalent cations and Ca²⁺. The AMPA- and kainate-selective ion charnels are permeable primarily to monovalent cations with only low permeability to Ca²⁺.

[0038] The Chloride Channel (ClC) Family

[0039] The ClC family is a large family consisting of dozens of sequenced proteins derived from Gram-negative and Gram-positive bacteria, cyanobacteria, archaea, yeast, plants and animals (Steinmeyer, K., et al., (1991), Nature 354: 301-304; Uchida, S., et al., (1993), J. Biol. Chem. 268: 3821-3824; Huang, M.-E., et al., (1994), J. Mol. Biol. 242: 595-598; Kawasaki, M., et al, (1994), Neuron 12: 597-604; Fisher, W. E., et al., (1995), Genomics. 29:598-606; and Foskett, J. K. (1998), Annu. Rev. Physiol. 60: 689-717). These proteins are essentially ubiquitous, although they are not encoded within genomes of Haemophilus influenzae, Mycoplasma genitalium, and Mycoplasma pneumoniae. Sequenced proteins vary in size from 395 amino acyl residues (M. jannaschii) to 988 residues (man). Several organisms contain multiple CIC family paralogues. For example, Synechocystis has two paralogues, one of 451 residues in length and the other of 899 residues. Arabidopsis thaliana has at least four sequenced paralogues, (775-792 residues), humans also have at least five paralogues (820-988 residues), and C. elegans also has at least five (810-950 residues). There are nine known members in mammals, and mutations in three of the corresponding genes cause human diseases. E. coli, Methanococcus jannaschii and Saccharomyces cerevisiae only have one ClC family member each. With the exception of the larger Synechocystis paralogue, all bacterial proteins are small (395-492 residues) while all eukaryotic proteins are larger (687-988 residues). These proteins exhibit 10-12 putative transmembrane a-helical spanners (TMSs) and appear to be present in the membrane as homodimers. While one member of the family, Torpedo ClC-O, has been reported to have two channels, one per subunit, others are believed to have just one.

[0040] All functionally characterized members of the ClC family transport chloride, some in a voltage-regulated process. These channels serve a variety of physiological functions (cell volume regulation; membrane potential stabilization; signal transduction; transepithelial transport, etc.). Different homologues in humans exhibit differing anion selectivities, i.e., ClC4 and ClC5 share a NO₃ ⁻>Cl⁻>Br⁻>I⁻ conductance sequence, while ClC3 has an I⁻>Cl⁻selectivity. The ClC4 and ClC5 channels and others exhibit outward rectifying currents with currents only at voltages more positive than +20 mV.

[0041] Animal Inward Rectifier K⁺ Channel (IRK-C) Family

[0042] IRK channels possess the “minimal channel-forming structure” with only a P domain, characteristic of the channel proteins of the VIC family, and two flanking transmembrane spanners (Shuck, M. E., et al., (1994), J. Biol. Chem. 269: 24261-24270; Ashen, M. D., et al., (1995), Am. J. Physiol. 268: H506-H511; Salkoff, L. and T. Jegla (1995), Neuron 15: 489-492; Aguilar-Bryan, L., et al., (1998), Physiol. Rev. 78: 227-245; Ruknudin, A., et al., (1998), J. Biol. Chem. 273: 14165-14171). They may exist in the membrane as homo- or heterooligomers. They have a greater tendency to let K⁺ flow into the cell than out. Voltage-dependence may be regulated by external K⁺, by internal Mg²⁺, by internal ATP and/or by G-proteins. The P-domains of IRK channels exhibit limhited sequence similarity to those of the VIC family, but this sequence similarity is insufficient to establish homology. Inward rectifiers play a role in setting cellular membrane potentials, and the closing of these channels upon depolarization permits the occurrence of long duration action potentials with a plateau phase. Inward rectifiers lack the intrinsic voltage sensing helices found in VIC family channels. In a few cases, those of Kir1.1a and Kir6.2, for example, direct interaction with a member of the ABC superfamily has been proposed to confer unique functional and regulatory properties to the heteromeric complex, including sensitivity to ATP. The SUR1 sulfonylurea receptor (spQ09428) is the ABC protein that regulates the Kir6.2 channel in response to ATP, and CFTR may regulate Kir1.1 a. Mutations in SUR1 are the cause of familial persistent hyperinsulinemic hypoglycemia in infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion in the pancreas.

[0043] ATP-gated Cation Channel (ACC) Family

[0044] Members of the ACC family (also called P2X receptors) respond to ATP, a functional neurotransmitter released by exocytosis from many types of neurons (North, R. A. (1996), Curr. Opin. Cell Biol. 8: 474-483; Soto, F., M. Garcia-Guzman and W. Stühmer (1997), J. Membr. Biol. 160: 91-110). They have been placed into seven groups (P2X₁-P2X₇) based on their pharmacological properties. These channels, which function at neuron-neuron and neuron-smooth muscle junctions, may play roles in the control of blood pressure and pain sensation. They may also function in lymphocyte and platelet, physiology. They are found only in animals.

[0045] The proteins of the ACC family are quite similar in sequence (>35% identity), but they possess 380-1000 amino acyl residues per subunit with variability in length localized primarily to the C-terminal domains. They possess two transmembrane spanners, one about 30-50 residues from their N-termini, the other near residues 320-340. The extracellular receptor domains between these two spanners (of about 270 residues) are well conserved with numerous conserved glycyl and cysteyl residues. The hydrophilic C-termini vary in length from 25 to 240 residues. They resemble the topologically similar epithelial Na⁺ channel (ENaC) proteins in possessing (a) N- and C-termini localized intracellularly, (b) two putative transmembrane spanners, (c) a large extracellular loop domain, and (d) many conserved extracellular cysteyl residues. ACC family members are, however, not demonstrably homologous with them. ACC channels are probably hetero- or homomultimers and transport small monovalent cations (Me⁺). Some also transport Ca²⁺; a few also transport small metabolites.

[0046] The Ryanodine-Inositol 1,4,5-triphosphate Receptor Ca²⁺ Channel (RIR-CaC) Family

[0047] Ryanodine (Ry)-sensitive and inositol 1,4,5-triphosphate (IP₃)-sensitive Ca²⁺-release channels function in the release of Ca²⁺ from intracellular storage sites in animal cells and thereby regulate various Ca²⁺-dependent physiological processes (Hasan, G. et al., (1992), Development. 116: 967-975; Michikawa, T., et al., (1994), J. Biol. Chem. 269: 9184-9189; Tunwell, R. E. A., (1996), Biochem. J. 318: 477-487; Lee, A. G. (1996) Biomembranes, Vol. 6, Transmembrane Receptors and Channels (A. G. Lee, ed.), JAI Press, Denver, Colo., pp 291-326; Mikoshiba, K., et al., (1996), J. Biochem. Biomem. 6: 273-289). Ry receptors occur primarily in muscle cell sarcoplasmic reticular (SR) membranes, and IP₃ receptors occur primarily in brain cell endoplasmic reticular (ER) membranes where they effect release of Ca²⁺ into the cytoplasm upon activation (opening) of the channel.

[0048] The Ry receptors are activated as a result of the activity of dihydropyridine-sensitive Ca²⁺ channels. The latter are members of the voltage-sensitive ion channel (VIC) family. Dihydropyridine-sensitive channels are present in the T-tubular systems of muscle tissues.

[0049] Ry receptors are homotetrameric complexes with each subunit exhibiting a molecular size of over 500,000 daltons (about 5,000 amino acyl residues). They possess C-terminal domains with six: putative transmembrane a helical spanners (TMSs). Putative pore-forming sequences occur between the fifth and sixth TMSs as suggested for members of the VIC family. The large N-terminal hydrophilic domains and the small C-terminal hydrophilic domains are localized to the cytoplasm. Low resolution 3-dimensional structural data are available. Mammals possess at least three isoforms that 11. probably arose by gene duplication and divergence before divergence of the mammalian species. Homologues are present in humans and Caenorabditis elegans.

[0050] IP₃ receptors resemble Ry receptors in many respects. (1) They are honiotetrameric complexes with each subunit exhibiting a molecular sizes of over 30000 daltons (about 2,700 amino acyl residues). (2) They possess C-terminal channel domains that are homologous to those of the Ry receptors. (3) The channel domains possess six putative TMSs and a putative channel lining region between TMSs 5 and 6. (4) Both the large N-terminal domains and the smaller. C-terminal tails face the cytoplasm. (5) They possess covalently linked carbohydrate on extracytoplasmic loops of the channel domains. (6) They have three currently recognized isoforms (types 1, 2, and 3) in mammals which are subject to differential regulation and have different tissue distributions.

[0051] IP₃ receptors possess three domains: N-terminal IP₃-binding domains, central coupling or regulatory domains and C-terminal channel domains. Channels are activated by IP₃ binding, and like the Ry receptors, the activities of the IP₃ receptor channels are regulated by phosphorylation of the regulatory domains, catalyzed by various protein kinases. They predominate in the endoplasmic reticular membranes of various cell types in the brain but have also been found in the plasma membranes of some nerve cells derived from a variety of tissues.

[0052] The channel domains of the Ry and IP₃ receptors comprise a coherent family that in spite of apparent structural similarities, do not show appreciable sequence similarity of the proteins of the VIC family. The Ry receptors and the IP₃ receptors cluster separately on the RIR-CaC family tree. They both have homologues in Drosophila. Based on the phylogenetic tree for the family, the family probably evolved in the following sequence: (1) A gene duplication event occurred that gave rise to Ry and IP₃ receptors in invertebrates. (2) Vertebrates evolved from invertebrates. (3) The three isoforms of each receptor arose as a result of two distinct gene duplication events. (4) These isoforms were transmitted to mammals before divergence of the mammalian species.

[0053] The Organellar Chloride Channel (O-ClC) Family

[0054] Proteins of the O-ClC family are voltage-sensitive chloride channels found in intracellular membranes but not the plasma membranes of animal cells (Landry, D, et al., (1993), J. Biol. Chem. 268: 14948-14955; Valenzuela, Set al., (1997), J. Biol. Chem. 272: 12575-12582; and Duncan, R. R., et al., (1997), J. Biol. Chem. 272: 23880-23886).

[0055] They are found in human nuclear membranes, and the bovine protein targets to the microsomes but not the plasma membrane, when expressed in Xenopus laevis, oocytes. These proteins are thought to function in the regulation of the membrane potential and in transepithelial ion absorption and secretion in the kidney. They possess two putative transmembrane a-helical spanners (TMSs) with cytoplasmic N- and C-termini and a large lumninal loop that may be glycosylated. The bovine protein is 437 amino acyl residues in length and has the two putative TMSs at positions 223-239 and 367-385. The human nuclear protein is much smaller (241 residues). A C. elegans homologue is 260 residues long.

[0056] Mitochondrial Solute Carrier Proteins

[0057] The novel human protein, and encoding gene; provided by the present invention is related to the mitochondrial solute carrier superfamily in general and the peroxisomal calcium-dependent solute carrier subfamily in particular. Specifically, the human protein of the present invention shows a high degree of similarity to rabbit peroxisomal calcium-dependent solute carrier proteins, which share 78% amino acid sequence homology in the C-terminal half with Grave disease carrier protein and 67% homology with human ADP/ATP translocase (Weber et al., Proc Natl Acad Sci USA 1997 Aug 5;94(16):8509-14).

[0058] Mitochondrial solute carrier proteins are found at the mitochondrial inner membrane and are important for metabolite transport across the membrane. Therefore, novel human mitochondrial solute carrier proteins/genes are medically and commercially useful for diagnosing and/or treating mitochondrial-associated diseases/disorders.

[0059] For a further review of mitochondrial solute carrier related proteins, such as the Aralar protein, see Crackower et al., Cytogenet. Cell Genet. 87: 197-198, 1999; del Arco et al., J. Biol. Chem. 273: 23327-23334, 1998; and Sanz et al., Cytogenet. Cell Genet. 89: 143-144, 2000.

[0060] Transporter proteins, particularly members of the mitochondrial solute carrier subfamily, are a major target for drug action and development. Accordingly, it is valuable to the field of pharmaceutical development to identify and characterize previously unknown transport proteins. The present invention advances the state of the art by providing previously unidentified human transport proteins.

SUMMARY OF THE INVENTION

[0061] The present invention is based in part on the identification of amino acid sequences of human transporter peptides and proteins that are related to the mitochondrial solute carrier subfamily, as well as allelic variants and other mammalian orthologs thereof. These unique peptide sequences, and nucleic acid sequences that encode these peptides, can be used as models for the development of human therapeutic targets, aid in the identification of therapeutic proteins, and serve as targets for the development of human therapeutic agents that modulate transporter activity in cells and tissues that express the transporter. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes.

DESCRIPTION OF THE FIGURE SHEETS

[0062]FIG. 1 provides the nucleotide sequence of a cDNA molecule that encodes the transporter protein of the present invention. (SEQ ID. NO: 1) In addition structure and functional information is provided, such as ATG start, stop and tissue distribution, where available, that allows one to readily determine specific uses of inventions based on this molecular sequence. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcindmas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes.

[0063]FIG. 2 provides the predicted amino acid sequence of the transporter of the present invention. (SEQ ID. NO:2) In addition structure and functional information such as protein family, function, and modification sites is provided where available, allowing one to readily determine specific uses of inventions based on this molecular sequence.

[0064]FIG. 3 provides genomic sequences that span the gene encoding the transporter protein of the present invention. (SEQ ID NO:3) In addition structure and functional information, such as intron/exon structure, promoter location, etc., is provided where available, allowing one to readily determine specific uses of inventions based on this molecular sequence. As illustrated in FIG. 3, SNPs were identified at 92 different nucleotide positions.

DETAILED DESCRIPTION OF THE INVENTION

[0065] General Description

[0066] The present invention is based on the sequencing of the human genome. During the sequencing and assembly of the human genome, analysis of the sequence information revealed previously unidentified fragments of the human genome that encode peptides that share structural and/or sequence homology to protein/peptide/domains identified and characterized within the art as being a transporter protein or part of a transporter protein and are related to the mitochondrial solute carrier subfamily. Utilizing these sequences, additional genomic sequences were assembled and transcript and/or cDNA sequences were isolated and characterized. Based on this analysis, the present invention provides amino acid sequences of human transporter peptides and proteins that are related to the mitochondrial solute carrier subfamily, nucleic acid sequences in the form of transcript sequences, cDNA sequences and/or genomic sequences that encode these transporter peptides and proteins, nucleic acid variation (allelic information), tissue distribution of expression, and information about the closest art known protein/peptide/domain that has structural or sequence homology to the transporter of the present invention.

[0067] In addition to being previously unknown, the peptides that are provided in the present invention are selected based on their ability to be used for the development of commercially important products and services. Specifically, the present peptides are selected based on homology and/or structural relatedness to known transporter proteins of the mitochondrial solute carrier subfamily and the expression pattern observed. Experimental data as provided in FIG. 1 indicates expression in humans in placenta, choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. The art has clearly established the commercial importance of members of this family of proteins and proteins that have expression patterns similar to that of the present gene. Some of the more specific features of the peptides of the present invention, and the uses thereof, are described herein, particularly in the Background of the Invention and in the annotation provided in the Figures, and/or are known within the art for each of the known mitochondrial solute carrier family or subfamily of transporter proteins.

[0068] Specific Embodiments

[0069] Peptide Molecules

[0070] The present invention provides nucleic acid sequences that encode protein molecules that have been identified as being members of the transporter family of proteins and are related to the mitochondrial solute carrier subfamily (protein sequences are provided in FIG. 2, transcript/cDNA sequences are provided in FIG. 1 and genomic sequences are provided in FIG. 3). The peptide sequences provided in FIG. 2, as well as the obvious variants described herein, particularly allelic variants as identified herein and using the information in FIG. 3, will be referred herein as the transporter peptides of the present invention, transporter peptides, or peptides/proteins of the present invention.

[0071] The present invention provides isolated peptide and protein molecules that consist of, consist essentially of, or comprising the amino acid sequences of the transporter peptides disclosed in the FIG. 2, (encoded by the nucleic acid molecule shown in FIG. 1, transcript/cDNA or FIG. 3, genomic sequence), as well as all obvious variants of these peptides that are within the art to make and use. Some of these variants are described in detail below.

[0072] As used herein, a peptide is said to be “isolated” or “purified” when it is substantially free of cellular material or free of chemical precursors or other chemicals. The peptides of the present invention can be purified to homogeneity or other degrees of purity. The level of purification will be based on the intended use. The critical feature is that the preparation allows for the desired function of the peptide, even if in the presence of considerable amounts of other components (the features of an isolated nucleic acid molecule is discussed below).

[0073] In some uses, “substantially free of cellular material” includes preparations of the peptide having less than about 30% (by dry weight) other proteins (i.e, contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the peptide is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20% of the volume of the protein preparation.

[0074] The language “substantially free of chemical precursors or other chemicals” includes preparations of the peptide in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language “substantially free of chemical precursors or other chemicals”, includes preparations of the transporter peptide having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.

[0075] The isolated transporter peptide can be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant), or synthesized using known protein synthesis methods. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. For example, a nucleic acid molecule encoding the transporter peptide is cloned into an expression vector, the expression vector introduced into a host cell and the protein expressed in the host cell. The protein can then be isolated from the cells by an appropriate purification scheme using standard protein purification techniques. Many of these techniques are described in detail below.

[0076] Accordingly, the present invention provides proteins that consist of the amino acid sequences provided in FIG. 2 (SEQ ID NO:2), for example, proteins encoded by the transcript/cDNA nucleic acid sequences shown in FIG. 1. (SEQ ID NO: 1) and the genomic sequences provided in FIG. 3 (SEQ ID NO:3). . The amino acid sequence of such a protein is provided in FIG. 2. A protein consists of an amino acid sequence when the amino acid sequence is the final amino acid sequence of the protein.

[0077] The present invention further provides proteins that consist essentially of the amino acid sequences provided in FIG. 2 (SEQ ID NO:2), for example, proteins encoded by the transcript/cDNA nucleic acid sequences shown in FIG. 1 (SEQ ID NO:1) and the genomnic sequences provided in FIG. 3 (SEQ ID NO:3). A protein consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues, for example from about 1: to about 100 or so additional residues, typically from 1 to about 20 additional residues in the final protein.

[0078] The present invention further provides proteins that comprise the amino acid sequences provided in FIG. 2 (SEQ ID NO:2), for example, proteins encoded by the transcript/cDNA nucleic acid sequences shown in FIG. 1 (SEQ ID NO: 1) and the genomic sequences provided in FIG. 3 (SEQ ID NO:3). A protein comprises an amino acid sequence when the amino acid sequence is at least part of the final amino acid sequence of the protein. In such a fashion, the protein can be only the peptide or have additional amino acid molecules, such as amino acid residues (contiguous encoded sequence) that are naturally associated with it or heterologous amino acid residues/peptide sequences. Such a protein can have a few additional amino acid residues or can comprise several hundred or more additional amino acids. The preferred classes of proteins that are comprised of the transporter peptides of the present invention are the naturally occurring mature proteins. A brief description of how various types of these proteins can be made/isolated is provided below.

[0079] The transporter peptides of the present invention can be attached to heterologous sequences to form chimeric or fusion proteins. Such chimeric and fusion proteins comprise a transporter peptide operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the transporter peptide. “Operatively linked” indicates that the transporter peptide and the heterologous protein are fused in frame. The heterologous protein can be fused to the N-terminus or C-terminus of the transporter peptide.

[0080] In some uses, the fusion protein does not affect the activity of the transporter peptide per se. For example, the fusion protein can include, but is not limited to, enzymatic fusion proteins, for example beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate the purification of recombinant transporter peptide. In certain host cells (e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence.

[0081] A chimeric or fusion protein can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different protein sequences are ligated together in-frame in accordance with conventional techniques. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence (see Ausubel et al. Current Protocols in Molecular Biology, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST protein). A transporter peptide-encoding nucleic acid can be cloned into, such an expression vector such that the fusion moiety is linked in-frame to the transporter peptide.

[0082] As mentioned above, the present invention also provides and enables obvious variants of the amino acid sequence of the proteins of the present invention, such as naturally occurring mature forms of the peptide, allelic/sequence variants of the peptides, non-naturally occurring recombinantly derived variants of the peptides, and orthologs and paralogs of the peptides. Such variants can readily be generated using art known techniques in the fields of recombinant nucleic acid technology and protein biochemistry. It is understood, however, that variants exclude any amino acid sequences disclosed prior to the invention.

[0083] Such variants can readily be identified/made using molecular techniques and the sequence information disclosed herein. Further, such variants can readily be distinguished from other peptides based on sequence and/or structural homology to the transporter peptides of the present invention. The degree of homology/identity present will be based primarily on whether the peptide is a functional variant or non-functional variant, the amount of divergence present in the paralog family and the evolutionary distance between the orthologs.

[0084] To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of a reference sequence is aligned for comparison purposes. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid. “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0085] The comparison of sequences and determination of percent identity and similarity between two sequences can be accomplished using a mathematical algorithm. (Computational Molecular Biology, Lesk, A. M. ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New. Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991). In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (Devereux, J., et al, Nucleic Acids Res. 12(1):387(1984)) (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS, 4:11-17.(1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM-120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0086] The nucleic acid and protein sequences of the present invention can further be used as a “query, sequence” to, perform a search against sequence databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (J. Mol. Biol. 215:403-10 (1990)). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength 3 to obtain amino, acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (Nucleic Acids Res.-25(17):3389-3402 (1997)). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0087] Full-length pre-processed forms, as well as mature processed forms; of proteins that comprise one of the peptides of the present invention can readily be identified as having complete sequence identity to one of the transporter peptides of the present invention as well as being encoded by the same genetic locus as the transporter peptide provided herein. The gene encoding the novel transporter protein of the present invention is located on a genome component that has been mapped to human chromosome 1 (as indicated in FIG. 3), which is supported by multiple lines of evidence, such as STS and BAC map data.

[0088] Allelic variants of a transporter peptide can readily be identified as being a human protein having a high degree (significant) of sequence homology/identity to at least a portion of the transporter peptide as well as being encoded by the same genetic locus as the transporter peptide provided herein. Genetic locus can readily be determined based on the genomic information provided in FIG. 3, such as the genomic sequence mapped to the reference human. The gene encoding the novel transporter protein of the present invention is located on a genome component that has been mapped to human chromosome 1 (as indicated in FIG. 3), which is supported by multiple lines of evidence, such as STS and BAC map data. As used herein, two proteins (or a region of the proteins) have significant homology when the amino acid sequences are typically at least about 70-80%, 80-90%, and more typically at least about 90-95% or more homologous. A significantly homologous amino acid sequence, according to the present invention, will be encoded by a nucleic acid sequence that will hybridize to a transporter peptide encoding nucleic acid molecule under stringent conditions as more fully described below.

[0089]FIG. 3, provides information on SNPs that have been found in the gene encoding the transporter protein of the present invention. SNPs were identified at 92 different nucleotide positions. SNPs such as these, particularly SNPs located 5′ of the ORF and in the first intron, may affect control/regulatory elements.

[0090] Paralogs of a transporter peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of the transporter peptide, as being encoded by a gene from humans, and as having similar activity or function. Two proteins will typically be considered paralogs when the amino acid sequences are typically at least about 60% or greater, and more typically at least about 70% or greater homology through a given region or domain. Such paralogs will be encoded by a nucleic acid sequence that Will hybridize to a transporter peptide encoding nucleic acid molecule under moderate to stringent conditions as more fully described below.

[0091] Orthologs of a transporter peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of the transporter peptide as well as being encoded by a gene from another organism. Preferred orthologs will be isolated from mammals, preferably primates, for the development of human therapeutic targets and agents. Such orthologs will be encoded by a nucleic acid sequence that will hybridize to a transporter peptide encoding nucleic acid molecule under moderate to stringent conditions, as more fully described below, depending on the degree of relatedness of the two organisms yielding the proteins.

[0092] Non-naturally occurring variants of the transporter peptides of the present invention can readily be generated using recombinant techniques. Such variants include, but are not limited to deletions, additions and substitutions in the amino acid sequence of the transporter peptide. For example, one class of substitutions are conserved amino acid substitution. Such substitutions are those that substitute a given amino acid in a transporter peptide by another amino acid of like characteristics. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gln; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found in Bowie et al., Science 247:1306-1310 (1990).

[0093] Variant transporter peptides can be fully functional or can lack function in one or more activities, e.g. ability to bind ligand, ability to transport ligand, ability to mediate signaling, etc. Fully functional variants typically contain only conservative variation or variation in non-critical residues or in non-critical regions. FIG. 2 provides the result of protein analysis and can be used to identify critical domains/regions. Functional variants can also contain substitution of similar amino acids that result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree.

[0094] Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, or truncation or a substitution, insertion, inversion, or deletion in a critical residue or critical region.

[0095] Amino acids that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham et al., Science 244:1081-1085.(1989)), particularly using the results provided in FIG. 2. The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as transporter activity or in assays such as an in vitro proliferative activity. Sites that are critical for binding partner/substrate binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith et al., J Mol. Biol. 224:899-904 (1992); de Vos et al. Science 255:306-312 (1992)).

[0096] The present invention further provides fragments of the transporter peptides, in addition to proteins and peptides that comprise and consist of such fragments, particularly those comprising the residues identified in FIG. 2. The fragments to which the invention pertains, however, are not to be construed as encompassing fragments that may be disclosed publicly prior to the present invention.

[0097] As used herein, a fragment comprises at least 8, 10, 12, 14, 16, or more contiguous amino acid residues from a transporter peptide. Such fragments can be chosen based on the ability to retain one or more of the biological activities of the transporter peptide or could be chosen for the ability to perform a function, e.g. bind a substrate or act as an immunogen. Particularly important fragments are biologically active fragments, peptides that are, for example, about 8 or more amino acids in length. Such fragments will typically comprise a domain or motif of the transporter peptide, e.g., active site, a transmembrane domain or a substrate-binding domain. Further, possible fragments include, but are not limited to, domain or motif containing fragments, soluble peptide fragments, and fragments containing immunogenic structures. Predicted domains and functional sites are readily identifiable by computer programs well known and readily available to those of skill in the art (e.g., PROSITE analysis). The results of one such analysis are provided in FIG. 2.

[0098] Polypeptides often contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Common modifications that occur naturally in transporter peptides are described in basic texts, detailed monographs, and the research literature, and they are well known to those of skill in the art (some of these features are identified in FIG. 2).

[0099] Known modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.

[0100] Such modifications are well known to those of skill in the art and have been described in great detail in the scientific literature. Several particularly common modifications, glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues; hydroxylation and ADP-ribosylation for instance, are described in most basic texts, such as Proteins—Structure and Molecular Properties, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993). Many detailed reviews are available on this subject, such as by Wold, F., Posttranslational Covalent Modification of Proteins, B. C. Johnson, Ed., Academic Press, New York 1-12 (1983); Seifter et al. (Meth. Enzymol. 182: 626-646(1990)) and Rattan et al. (Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

[0101] Accordingly, the transporter peptides of the present invention also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature transporter peptide is fused with another compound, such as a compound to increase the half-life of the transporter peptide (for example, polyethylene glycol), or in which the additional amino acids are fused to the mature transporter peptide, such as a leader or secretory sequence or a sequence for purification of the mature transporter peptide or a pro-protein sequence.

[0102] Protein/Peptide Uses

[0103] The proteins of the present invention can be used in substantial and specific as says related to, the functional information provided in the Figures: to raise antibodies or to elicit an other immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its binding partner or ligand) in biological fluids; and as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state). Where the protein binds or potentially binds to another protein or ligand (such as, for example, in a transporter-effector protein interaction or transporter-ligand interaction), the protein can be used to identify the binding partner/ligand so as to develop a system to identify inhibitors of the binding interaction. Any or all of these uses are capable of being developed into reagent grade or kit format for commercialization as commercial products.

[0104] Methods for performing the uses listed above are well known to those skilled in the art. References disclosing such methods include “Molecular Cloning: A Laboratory Manual”, 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E. F. Fritsch and T. Maniatis eds., 1989, and “Methods in Enzymology Guide to Molecular Cloning Techniques”, Academic Press, Berger, S. L. and A. R. Kimmel eds., 1987.

[0105] The potential uses of the peptides of the present invention are based primarily on the source of the protein as Well as the class/action of the protein. For example, transporters isolated from humans and their human/mammalian orthologs serve as targets for identifying agents for use in mammalian therapeutic applications, e.g. a human drug, particularly in modulating a biological or pathological response in a-cell or tissue that expresses the transporter. Experimental data as provided in FIG. 1 indicates that the transporter proteins of the present invention are expressed in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, and ovary fibrotheomas, as indicated by virtual northern blot analysis. In addition, PCR-based tissue screening panels indicate expression in leukocytes. A large percentage of pharmaceutical agents are being developed that modulate the activity of transporter proteins, particularly members of the mitochondrial solute carrier subfamily (see Background of the Invention). The structural and functional information provided in the Background and Figures provide specific and substantial uses for the molecules of the present invention, particularly in combination with the expression information provided in FIG. 1. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. Such uses can readily be determined using the information provided herein, that known in the art and routine experimentation.

[0106] The proteins of the present invention (including variants and fragments that may have been disclosed prior to the present invention) are useful for biological assays related to transporters that are related to members of the mitochondrial solute carrier subfamily. Such assays involve any of the known transporter functions or activities or properties useful for diagnosis and treatment of transporter-related conditions that are specific for the subfamily of transporters that the one of the present invention belongs to, particularly in cells and tissues that express the transporter. Experimental data as provided in FIG. 1 indicates that the transporter proteins of the present invention are expressed in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, and ovary fibrotheomas, as indicated by virtual northern blot analysis. In addition, PCR-based tissue screening panels indicate expression in leukocytes. The proteins of the present invention are also useful in drug screening assays, in cell-based or cell-free systems ((Hodgson, Bio/technology, 1992, Sep 10(9);973-80). Cell-based systems can be native, i.e., cells that normally express the transporter, as a biopsy or expanded in cell culture. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. In an alternate embodiment, cell-based assays involve recombinant host cells expressing the transporter protein.

[0107] The polypeptides can be used to identify compounds that modulate transporter activity of the protein in its natural state or an altered form that causes a specific disease or pathology associated with the transporter. Both the transporters of the present invention and appropriate variants and fragments can be used in high-throughput screens to assay candidate compounds for the ability to bind to the transporter. These compounds can be further screened against a functional transporter to determine the effect of the compound on the transporter activity. Further, these compounds can be tested in animal or invertebrate systems to determine activity/effectiveness. Compounds can be identified that activate (agonist) or inactivate (antagonist) the transporter to a desired degree.

[0108] Further, the proteins of the present invention can be used to screen a compound for the ability to stimulate or inhibit interaction between the transporter protein and a molecule that normally interacts with the transporter protein, e.g. a substrate or a component of the signal pathway that the transporter protein normally interacts (for example, another transporter). Such assays typically include the steps of combining the transporter protein with a candidate compound under conditions that allow the transporter protein, or fragment, to interact with the target molecule, and to detect the formation of a complex between the protein and the target or to detect the biochemical consequence of the interaction with the transporter protein and the target, such as any of the associated effects of signal transduction such as changes in membrane potential, protein phosphorylation, cAMP turnover, and adenylate cyclase activation, etc.

[0109] Candidate compounds include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991); Houghten et al., Nature. 354:84-86 (1991)) and combinatorial chemistry derived molecular libraries made of D- and/or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab′)₂, Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries).

[0110] One candidate compound is a soluble fragment of the receptor that competes for ligand binding. Other candidate compounds include mutant transporters or appropriate fragments containing mutations that affect transporter function and thus compete for ligand. Accordingly, a fragment that competes for ligand, for example with a higher affinity, or a fragment that binds ligand but does not allow release, is encompassed by the invention.

[0111] The invention further includes other end point assays to identify compounds that modulate (stimulate or inhibit) transporter activity. The assays typically involve an assay of events in the signal transduction pathway that indicate transporter activity. Thus, the transport of a ligand, change in cell membrane potential, activation of a protein, a change in the expression of genes that are up- or down-regulated in response to the transporter protein dependent signal cascade can be assayed.

[0112] Any of the biological or biochemical functions mediated by the transporter can be used as an endpoint assay. These include all of the biochemical or biochemical/biological events described herein, in the references cited herein, incorporated by reference for these endpoint assay targets, and other functions known to those of ordinary skill in the art or that can be readily identified using the information provided in the Figures, particularly FIG. 2. Specifically, a biological function of a cell or tissues that expresses the transporter can be assayed. Experimental data as provided in FIG. 1 indicates that the transporter proteins of the present invention are expressed in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, and ovary fibrotheomas, as indicated by virtual northern blot analysis. In addition, PCR-based tissue screening panels indicate expression in leukocytes.

[0113] Binding and/or activating compounds can also be screened by using chimeric transporter proteins in which the amino terminal extracellular domain, or parts thereof the entire transmembrane domain or subregions, such as any of the seven transmembrane segments or any of the intracellular or extracellular loops and the carboxy terminal intracellular domain, or parts thereof, can be replaced by heterologous domains or subregions. For example, a ligand-binding region can be used that interacts with a different ligand then that which is recognized by the native transporter. Accordingly, a different set of signal transduction components is available as an end point assay for activation. This allows for assays to be performed in other than the specific host cell from which the transporter is derived.

[0114] The proteins of the present invention are also useful in competition binding assays in methods designed to discover compounds that interact with the transporter (e.g. binding partners and/or ligands). Thus, a compound is exposed to a transporter polypeptide under conditions that allow the compound to bind or to otherwise interact with the polypeptide. Soluble transporter polypeptide is also added to the mixture. If the test compound interacts with the soluble transporter polypeptide, it decreases the amount of complex formed or activity from the transporter target. This type of assay is particularly useful in cases in which compounds are sought that interact with specific regions of the transporter. Thus, the soluble polypeptide that competes with the target transporter region is designed to contain peptide sequences corresponding to the region of interest.

[0115] To perform cell free drug screening assays, it is sometimes desirable to immobilize either the transporter protein, or fragment, or its target molecule to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay.

[0116] Techniques for immobilizing proteins on matrices can be used in the drug screening assays. In one embodiment, a fusion protein can be provided which adds a domain that allows the protein to be bound to a matrix. For example, glutathione-S-transferase fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g., ³⁵S-labeled) and the candidate compound, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads are washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of transporter-binding protein found in the bead fraction quantitated from the gel using standard electrophoretic techniques. For example, either the polypeptide or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin using techniques well known in the art. Alternatively, antibodies reactive with the protein but which do not interfere with binding of the protein to its target molecule can be derivatized to the wells of the plate, and the protein trapped in the wells by antibody conjugation. Preparations of a transporter-binding protein and a candidate compound are incubated in the transporter protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the transporter protein target molecule, or which are reactive with transporter protein and compete with the target molecule, as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the target molecule.

[0117] Agents that modulate one of the transporters of the present invention can be identified using one or more of the above assays, alone or in combination. It is generally preferable to use a cell-based or cell free system first and then confirm activity in an animal or other model system. Such model systems are well known in the art and can readily be employed in this context.

[0118] Modulators of transporter protein activity identified according to these drug screening assays can be used to treat a subject with a disorder mediated by the transporter pathway, by treating cells or tissues that express the transporter. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. These methods of treatment include the steps of administering a modulator of transporter activity in a pharmaceutical composition to a subject in need of such treatment, the modulator being identified as described herein.

[0119] In yet another aspect of the invention, the transporter; proteins can be used as “bait proteins” in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura et al. (1993) J Biol. Chem. 268:12046-12054; Bartel et al. (1993) Biotechniques 14:920-924; Iwabuchi et. al. (1993) Oncogene 8:1693-1696; and Brent WO94/10300), to identify other proteins, which bind to or interact with the transporter and are involved in transporter activity. Such transporter-binding proteins are also likely to be involved in the propagation of signals by the transporter proteins or transporter targets as, for example, downstream elements of a transporter-mediated signaling pathway. Alternatively, such transporter-binding proteins are likely to be transporter inhibitors.

[0120] The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for a transporter protein is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo forming a transporter-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected a cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene which encodes the protein which interacts with the transporter protein.

[0121] This invention further pertains to novel agents identified by the above-described screening assays. Accordingly, it is within the scope of this invention to further use an agent identified as described herein in an appropriate animal model. For example, an agent identified as described herein (e.g., a transporter-modulating agent, an antisense transporter nucleic acid molecule, a transporter-specific antibody, or a transporter-binding partner) can be used in an animal or other model to determine the efficacy, toxicity, or side effects of treatment with such an agent. Alternatively, an agent identified as described herein can be used in an animal or other model to determine the mechanism of action of such an agent. Furthermore, this invention pertains to uses of novel agents identified by the above-described screening assays for treatments as described herein.

[0122] The transporter proteins of the present invention are also useful to provide a target for diagnosing a disease or predisposition to disease mediated by the peptide. Accordingly, the invention provides methods for detecting the presence, or levels of, the protein (or encoding mRNA) in a cell, tissue, or organism. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. The method involves contacting a biological sample with a compound capable of interacting with the transporter protein such that the interaction can be detected. Such an assay can be provided in a single detection format or a multi-detection format such as an antibody chip array.

[0123] One agent for detecting a protein in a sample is an antibody capable of selectively binding to protein. A biological sample includes tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.

[0124] The peptides of the present invention also provide targets for diagnosing active protein activity, disease, or predisposition to disease, in a patient having a variant peptide, particularly activities and conditions that are known for other members of the family of proteins to which the present one belongs. Thus, the peptide can be isolated from a biological sample and assayed for the presence of a genetic mutation that results in aberrant peptide. This includes amino acid substitution, deletion, insertion, rearrangement, (as the result of aberrant splicing events), and inappropriate post-translational modification. Analytic methods include altered electrophoretic mobility, altered tryptic peptide digest, altered transporter activity, in cell-based or cell-free assay, alteration in ligand or antibody-binding pattern, altered isoelectric point, direct amino acid sequencing, and any other of the known assay techniques useful for detecting mutations in a protein. Such an assay can be provided in a single detection format or a multi-detection format such as an antibody chip array.

[0125] In vitro techniques for detection of peptide include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence using a detection reagent, such as an antibody or protein binding agent. Alternatively, the peptide can be detected in vivo in a subject by introducing into the subject a labeled anti-peptide antibody or other types of detection agent. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. Particularly useful are methods that detect the allelic variant of a peptide expressed in a subject and methods which detect fragments of a peptide in a sample.

[0126] The peptides are also useful in pharmacogenomic analysis. Pharmacogenomics deal with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See, e.g., Eichelbaum, M. (Clin. Exp. Pharmacol. Physiol. 23(10-11):983-985 (1996)), and Linder, M. W. (Clin. Chem., 43(2):254-266 (1997)). The clinical outcomes of these variations result in severe toxicity of therapeutic drugs in certain individuals' or therapeutic failure of drugs in certain individuals, as a result of individual variation in metabolism. Thus, the genotype of the individual can determine the way a therapeutic compound acts on the body or the way the body metabolizes the compound. Further, the activity of drug metabolizing enzymes effects both the intensity and duration of drug action. Thus, the pharmacogenomics of the individual permit the selection of effective compounds and effective dosages of such compounds for prophylactic or therapeutic treatment based on the individual's genotype. The discovery of genetic polymorphisms in some drug metabolizing enzymes has explained why some patients do not obtain the expected drug effects, show an exaggerated drug effect, or experience serious toxicity from standard drug dosages. Polymorphisms can be expressed in the phenotype of the extensive metabolizer and the phenotype of the poor metabolizer. Accordingly, genetic polymorphism may lead to allelic-protein variants of the transporter protein in which one or more of the transporter functions in one population is different from those in another population. The peptides thus allow a target to ascertain a genetic predisposition that can affect treatment modality. Thus, in a ligand-based treatment, polymorphism may give rise to amino terminal extracellular domains and/or other ligand-binding regions that are more or less active in ligand binding, and transporter activation. Accordingly, ligand dosage would necessarily be modified to maximize the therapeutic effect within a given population containing a polymorphism. As an alternative to genotyping, specific polymorphic peptides could be identified.

[0127] The peptides are also useful for treating a disorder characterized by an absence of, inappropriate, or unwanted expression of the protein. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. Accordingly, methods for treatment include the use of the transporter protein or fragments.

[0128] Antibodies

[0129] The invention also provides antibodies that selectively bind to one of the peptides of the present invention, a protein comprising such a peptide, as well as variants and fragments thereof. As used herein, an antibody selectively binds a target peptide when it binds the target peptide and does not significantly bind to unrelated proteins. An antibody is still considered to selectively bind a peptide even if it also binds to other proteins that are not substantially homologous with the target peptide so long as such proteins share homology with a fragment or domain of the peptide target of the antibody. In this case, it would be understood that antibody binding to the peptide is still selective despite some degree of cross-reactivity.

[0130] As used herein, an antibody is defined in terms consistent with that recognized within the art: they are multi-subunit proteins produced by a mammalian organism in response to an antigen challenge. The antibodies of the present invention include polyclonal antibodies and monoclonal antibodies, as well as fragments of such antibodies, including, but not limited to, Fab or F(ab′)₂, and Fv fragments.

[0131] Many, methods are known for generating and/or identifying antibodies to a given target peptide. Several such methods are described by Harlow, Antibodies, Cold Spring Harbor Press, (1989).

[0132] In general, to generate antibodies, an isolated peptide is used as an immunogen and is administered to a mammalian organism, such as a rat, rabbit or mouse. The full-length protein; an antigenic peptide fragment or a fusion protein can be used. Particularly important fragments are those covering functional domains, such as the domains identified in FIG. 2, and domain of sequence homology or divergence amongst the family, such as those that can readily be identified using protein alignment methods and as presented in the Figures.

[0133] Antibodies are preferably prepared from regions or discrete fragments of the transporter proteins. Antibodies can be prepared from any region of the peptide as described herein. However, preferred regions will include those involved in function/activity and/or transporter/binding partner interaction. FIG. 2 can be used to identify particularly important regions while sequence alignment can be used to identify conserved and unique sequence fragments.

[0134] An antigenic fragment will typically comprise at least 8 contiguous amino acid residues. The antigenic peptide can comprise, however, at least 10, 12, 14, 16 or more amino acid residues. Such fragments can be selected on a physical property, such as fragments correspond to regions that are located on the surface of the protein, e.g., hydrophilic regions or can be selected based on sequence uniqueness (see FIG. 2).

[0135] Detection on an antibody of the present invention can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or ³H.

[0136] Antibody Uses

[0137] The antibodies can be used to isolate one of the proteins of the present invention by standard techniques, such as affinity chromatography or immunoprecipitation. The antibodies can facilitate the purification of the natural protein from cells and recombinantly produced protein expressed in host cells. In addition, such antibodies are useful to detect the presence of one of the proteins of the present invention in cells or tissues to determine the pattern of expression of the protein among various tissues in an organism and over the course of normal development. Experimental data as provided in FIG. 1 indicates that the transporter proteins of the present invention are expressed in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, and ovary fibrotheomas, as indicated by virtual northern blot analysis. In addition, PCR-based tissue screening panels indicate expression in leukocytes. Further, such antibodies can be used to detect protein in situ, in vitro, or in a cell lysate or supernatant in order to evaluate the abundance and pattern of expression. Also, such antibodies can be used to assess abnormal tissue distribution or abnormal expression during development or progression of a biological condition. Antibody detection of circulating fragments of the full length protein can be used to identify turnover.

[0138] Further, the antibodies can be used to assess expression in disease states such as in active stages of the disease or in an individual with a predisposition toward disease related to the protein's function. When a disorder is caused by an inappropriate tissue distribution, developmental expression, level of expression of the protein, or expressed/processed form, the antibody can be prepared against the normal protein. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. If a disorder is characterized by a specific mutation in the protein, antibodies specific for this mutant protein can be used to assay for the presence of the specific mutant protein.

[0139] The antibodies can also be used to assess normal and aberrant subcellular localization of cells in the various tissues in an organism. Experimental data as provided in FIG. 1, indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. The diagnostic-uses can be applied, not only in genetic testing, but also in monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting expression level or the presence of aberrant sequence and aberrant tissue distribution or developmental expression, antibodies directed against the protein or relevant fragments can be used to monitor therapeutic efficacy.

[0140] Additionally, antibodies are useful in pharmacogenomic analysis. Thus, antibodies prepared against polymorphic proteins can be used to identify individuals that require modified treatment modalities. The antibodies are also useful as diagnostic tools as an immunological marker for aberrant protein analyzed by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays known to those in the art.

[0141] The antibodies are also useful for tissue typing. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. Thus, where a specific protein has been correlated with expression in a specific tissue, antibodies that are specific for this protein can be used to identify a tissue type.

[0142] The antibodies are also useful for inhibiting protein function, for example, blocking the binding of the transporter peptide to a binding partner such as a ligand or protein binding partner. These uses can also be applied in a therapeutic context in which treatment involves inhibiting the protein's function. An antibody can be used, for example, to block binding, thus modulating (agonizing or antagonizing) the peptides activity. Antibodies can be prepared against specific fragments containing sites required for function or against intact protein that is associated with a cell or cell membrane. See FIG. 2 for structural information relating to the proteins of the present invention.

[0143] The invention also encompasses kits for using antibodies to detect the presence of a protein in a biological sample. The kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting protein in a biological sample; means for determining the amount of protein in the sample; means for comparing the amount of protein in the sample with a standard; and instructions for use: Such a kit can be supplied to detect a single protein or epitope or can be configured to detect one of a multitude of epitopes, such as in an antibody detection array. Arrays are described in detail below for nucleic acid arrays and similar methods have been developed for antibody arrays.

[0144] Nucleic Acid Molecules

[0145] The present invention further provides isolated nucleic acid molecules that encode a transporter peptide or protein of the present invention (cDNA, transcript and genomic sequence). Such nucleic acid molecules will consist of, consist essentially of, or comprise a nucleotide sequence that encodes one of the transporter peptides of the present invention, an allelic variant thereof, or an ortholog or paralog thereof.

[0146] As used herein, an “isolated” nucleic acid molecule is one that is separated from other nucleic acid present in the natural source of the nucleic acid. Preferably, an “isolated” nucleic acid is free of sequences that naturally flank the nucleic acid (i.e., sequences located at the 5′ and 3′ ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. However, there can be some flanking nucleotide sequences, for example up to about 5 KB, 4 KB, 3 KB, 2 KB, or 1 KB or less, particularly contiguous peptide encoding sequences and peptide encoding sequences within the same gene but separated by introns in the genomic sequence. The important point is that the nucleic acid is isolated from remote and unimportant flanking sequences such that it can be subjected to the specific manipulations described herein such as recombinant expression, preparation of probes and primers, and other uses specific to the nucleic acid sequences.

[0147] Moreover, an “isolated” nucleic acid molecule, such as a transcript/cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. However, the nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered isolated.

[0148] For example, recombinant DNA molecules contained in a vector are considered isolated. Further examples of isolated DNA molecules include recombinant DNA molecules maintained in heterologous host cells or purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the isolated DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.

[0149] Accordingly, the present invention provides nucleic acid molecules that consist of the nucleotide sequence shown in FIG. 1 or 3 (SEQ ID NO: 1, transcript sequence and SEQ ID NO:3, genomic sequence), or any nucleic acid molecule that encodes the protein provided in FIG. 2, SEQ ID NO:2. A nucleic acid molecule consists of a nucleotide sequence when the nucleotide sequence is the complete nucleotide sequence of the nucleic acid molecule.

[0150] The present invention further provides nucleic acid molecules that consist essentially of the nucleotide sequence shown in FIG. 1 or 3 (SEQ ID NO: 1, transcript sequence and SEQ ID. NO:3, genomic sequence), or any nucleic acid molecule that encodes the protein provided in FIG. 2, SEQ. ID NO:2. A nucleic acid molecule consists essentially of a nucleotide sequence when such a nucleotide sequence is present with only a few additional nucleic acid residues in the final nucleic acid molecule.

[0151] The present invention further provides nucleic acid molecules that comprise the nucleotide sequences shown in FIG. 1 or 3 (SEQ ID. NO:1, transcript sequence and SEQ ID NO:3, genomic sequence), or any nucleic acid molecule that encodes the protein provided in FIG. 2, SEQ ID. NO:2. A nucleic acid molecule comprises a nucleotide sequence when the nucleotide sequence is at least part of the final nucleotide sequence of the nucleic acid molecule. In such a fashion, the nucleic acid molecule can be only the nucleotide sequence or have additional nucleic acid residues, such as nucleic acid residues that are naturally associated with it or heterologous nucleotide sequences. Such a nucleic acid molecule can have a few additional nucleotides or can comprise several hundred or more additional nucleotides. A brief description of how various types of these nucleic acid molecules can be readily made/isolated is provided below.

[0152] In FIGS. 1 and 3, both coding and non-coding sequences are provided. Because of the source of the present invention, humans genomic sequence (FIG. 3) and cDNA/transcript sequences (FIG. 1), the nucleic acid molecules in the Figures will contain genomic intronic sequences, 5′ and 3′ non-coding sequences, gene regulatory regions and non-coding intergenic sequences. In general such sequence features are either noted in FIGS. 1 and 3, or can readily be identified using computational tools known in the art. As discussed below, some of the non-coding regions, particularly gene regulatory elements such as promoters, are useful for a variety of purposes, e.g. control of heterologous gene expression, target for identifying gene activity modulating compounds, and are particularly claimed as fragments of the genomic sequence provided herein The isolated nucleic acid molecules can encode the mature protein plus additional amino or carboxyl-terminal amino acids, or amino acids interior to the mature peptide (when the mature form has more than one peptide chain, for instance). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half-life or facilitate manipulation of a protein for assay, or production, among other things. As generally is the case in situ, the additional amino acids may be processed away from the mature protein by cellular enzymes.

[0153] As mentioned above, the isolated nucleic acid molecules include, but are not limited to, the sequence encoding the transporter peptide alone, the sequence encoding the mature peptide and additional coding sequences, such as a leader or secretory sequence (e.g., a pre-pro or pro-protein sequence), the sequence encoding the mature peptide, with or without the additional coding sequences, plus additional non-coding sequences, for example introns and non-coding 5′ and 3′ sequences such as transcribed but non-translated sequences that play a role in transcription, mRNA processing (including splicing, and polyadenylation signals), ribosome binding and stability of mRNA. In addition, the nucleic acid molecule may be fused to a marker sequence encoding, for example, a peptide that facilitates purification.

[0154] Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form DNA, including cDNA and genomic DNA obtained by cloning or produced by chemical synthetic techniques or by a combination thereof. The nucleic acid, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the non-coding strand (anti-sense strand).

[0155] The invention further provides nucleic acid molecules that encode fragments of the peptides of the present invention as well as nucleic acid molecules that encode obvious variants of the transporter proteins of the present invention that are described above. Such nucleic acid molecules may be naturally occurring, such as allelic variants (same locus), paralogs (different locus), and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Such non-naturally occurring variants may be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells, or organisms. Accordingly, as discussed above, the variants can contain nucleotide substitutions, deletions, inversions and insertions. Variation can occur in either or both the coding and non-coding regions. The variations can produce both conservative and non-conservative amino acid substitutions.

[0156] The present invention further provides non-coding fragments of the nucleic acid molecules provided in FIGS. 1 and 3. Preferred non-coding fragments include, but are not limited to, promoter sequences, enhancer sequences, gene modulating sequences and gene termination sequences. Such fragments are useful in controlling heterologous gene expression and in developing screens to identify gene-modulating agents. A promoter can readily be identified as being 5′ to the ATG start site in the genomic sequence provided in FIG. 3.

[0157] A fragment comprises a contiguous nucleotide sequence greater than 12 or more nucleotides. Further, a fragment could at least 30, 40, 50, 100, 250 or 500 nucleotides in length. The length of the fragment will be based on its intended use. For example, the fragment can encode epitope bearing regions of the peptide, or can be useful as DNA probes and primers. Such fragments can be isolated using the known nucleotide sequence to synthesize an oligonucleotide probe. A labeled probe can then be used to screen a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid corresponding to the coding region. Further, primers can be used in PCR reactions to clone specific regions of gene.

[0158] A probe/primer typically comprises substantially a purified oligonucleotide or oligonucleotide pair. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 20, 25, 40, 50 or more consecutive nucleotides.

[0159] Orthologs, homologs, and allelic variants can be identified using methods well known in the art. As described in the Peptide Section, these variants comprise a nucleotide sequence encoding a peptide that is typically 60-70%, 70-80%, 80-90%, and more typically at least about 90-95% or more homologous to the nucleotide sequence shown in the Figure sheets or a fragment of this sequence. Such nucleic acid molecules can readily be identified as being able to hybridize under moderate to stringent conditions, to the nucleotide sequence shown in the Figure sheets or a fragment of the sequence. Allelic variants can readily be determined by genetic locus of the encoding gene. The gene encoding the novel transporter protein of the present invention is located on a genome component that has been mapped to human chromosome 1 (as indicated in FIG. 3), which is supported by multiple lines of evidence, such as STS and BAC map data.

[0160]FIG. 3 provides information on SNPs that have been found in the gene encoding the transporter protein of the present invention. SNPs were identified at 92 different nucleotide positions. SNPs such as these, particularly SNPs located 5′, of the ORF and in the first intron, may affect control/regulatory elements.

[0161] As used herein, the term “hybridizes under stringent conditions” is intended to describe conditions for hybridization and washing under which nucleotide sequences encoding a peptide at least 60-70% homologous to each other typically remain hybridized to each other. The conditions can be such that sequences at least about 60%, at least about 70%, or at least about 80% or more homologous to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. One example of stringent hybridization conditions are hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45C, followed by one or more washes in 0.2×SSC, 0.1% SDS at 50-65C. Examples of moderate to low stringency hybridization conditions are well known in the art.

[0162] Nucleic Acid Molecule Uses

[0163] The nucleic acid molecules of the present invention are useful for probes, primers, chemical intermediates, and in biological assays. The nucleic acid molecules are useful as a hybridization probe for messenger RNA, transcript/cDNA and genomic DNA to isolate full-length cDNA and genomic clones encoding the peptide described in FIG. 2 and to isolate cDNA and genomic clones that correspond to variants (alleles, orthologs, etc.) producing the same or related peptides shown in FIG. 2. As illustrated in FIG. 3, SNPs were identified at 92 different nucleotide positions.

[0164] The probe can correspond to any sequence along the entire length of the nucleic acid molecules provided in the Figures. Accordingly, it could be derived from 5′ noncoding regions, the coding region, and 3′ noncoding regions. However, as discussed, fragments are not to be construed as encompassing fragments disclosed prior to the present invention.

[0165] The nucleic acid molecules are also useful as primers for PCR to amplify any given region of a nucleic acid molecule and are useful to synthesize antisense molecules of desired length and sequence.

[0166] The nucleic acid molecules are also useful for constructing recombinant vectors. Such vectors include expression vectors that express a portion of, or all of, the peptide sequences. Vectors also include insertion vectors, used to integrate into another nucleic acid molecule sequence, such as into the cellular genome, to alter in situ expression of a gene and/or gene product. For example, an endogenous coding sequence can be replaced via homologous recombination with all or part of the coding region containing one or more specifically introduced mutations.

[0167] The nucleic acid molecules are also useful for expressing antigenic portions of the proteins.

[0168] The nucleic acid molecules are also useful as probes for determining the chromosomal positions of the nucleic acid molecules by means of in situ hybridization methods. The gene encoding the novel transporter protein of the present invention is located on a genome component that has been mapped, to human chromosome 1. (as indicated in FIG. 3), which is supported by multiple lines of evidence, such as STS and BAC map data.

[0169] The nucleic acid molecules are also useful in making vectors containing the gene regulatory regions of the nucleic acid molecules of the present invention.

[0170] The nucleic acid molecules are also useful for designing ribozymes corresponding to all, or a part, of the mRNA produced from the nucleic acid molecules described herein.

[0171] The nucleic acid molecules are also useful for making vectors that express part, or all, of the peptides.

[0172] The nucleic acid molecules are also useful for constructing host cells expressing a part, or all, of the nucleic acid molecules and peptides.

[0173] The nucleic acid molecules are also useful for constructing transgenic animals expressing all, or a part, of the nucleic acid molecules and peptides.

[0174] The nucleic acid molecules are also useful as hybridization probes for determining the presence, level, form and distribution of nucleic acid expression. Experimental data as provided in FIG. 1 indicates that the transporter proteins of the present invention are expressed in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, and ovary fibrotheomas, as indicated by virtual northern blot analysis. In addition, PCR-based tissue screening panels indicate expression in leukocytes.

[0175] Accordingly, the probes can be used to detect the presence of, or to determine levels of, a specific nucleic acid molecule in cells, tissues, and in organisms. The nucleic acid whose level is determined can be DNA or RNA. Accordingly, probes corresponding to the peptides described herein can be used to assess expression and/or gene copy number in a given cell, tissue, or organism. These uses are relevant for diagnosis of disorders involving an increase or decrease in transporter protein expression relative to normal results.

[0176] In vitro, techniques for detection of mRNA include Northern hybridizations and in, situ hybridizations. In vitro techniques for detecting DNA include Southern hybridizations and in situ hybridization.

[0177] Probes can be used as apart of a diagnostic test kit for identifying cells or tissues that express a transporter protein, such as by measuring a level of a transporter-encoding nucleic acid in a sample of cells from a subject e.g., mRNA or genomic DNA, or determining if a transporter gene has been mutated. Experimental data as provided in FIG. 1, indicates that the transporter proteins of the present invention are expressed in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, and ovary fibrotheomas, as indicated by virtual northern blot analysis. In addition, PCR-based tissue screening panels indicate expression in leukocytes.

[0178] Nucleic acid expression assays are useful for drug screening to identify compounds that modulate transporter nucleic acid expression.

[0179] The invention thus provides a method for identifying a compound that can be used to treat a disorder associated with nucleic acid expression of the transporter gene, particularly biological and pathological processes that are mediated by the transporter in cells and tissues that express it. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes. The method typically includes assaying the ability of the compound to modulate the expression of the transporter nucleic acid and thus identifying a compound that can be used to treat a disorder characterized by undesired transporter nucleic acid expression. The assays can be performed in cell-based and cell-free systems. Cell-based assays include cells naturally expressing the transporter nucleic acid or recombinant cells genetically engineered to express specific nucleic acid sequences.

[0180] The assay for transporter nucleic acid expression can involve direct assay of nucleic acid levels, such as mRNA levels, or on collateral compounds involved in the signal pathway. Further, the expression of genes that are up- or down-regulated in response to the transporter protein signal pathway can also be assayed. In this embodiment the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.

[0181] Thus, modulators of transporter gene expression can be identified in a method wherein a cell is contacted with a candidate compound and the expression of mRNA determined. The level of expression of transporter mRNA in the presence of the candidate compound is compared to the level of expression of transporter mRNA in the absence of the candidate compound. The candidate compound can then be identified as a modulator of nucleic acid expression based on this comparison and be used, for example to treat a disorder characterized by aberrant nucleic acid expression. When expression of mRNA is statistically significantly greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of nucleic acid expression. When nucleic acid expression is statistically significantly less in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of nucleic acid expression.

[0182] The invention further provides methods of treatment, with the nucleic acid as a target, using a compound identified through drug screening as a gene modulator to modulate transporter nucleic acid expression in cells and tissues that express the transporter. Experimental data as provided in FIG. 1 indicates that the transporter proteins of the present invention are expressed in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, and ovary fibrotheomas, as indicated by virtual northern blot analysis. In addition, PCR-based tissue screening panels indicate expression in leukocytes. Modulation includes both up-regulation (i.e. activation or agonization) or down-regulation (suppression or antagonization) or nucleic acid expression.

[0183] Alternatively, a modulator for transporter nucleic acid expression can be a small molecule or drug identified using the screening assays described herein as long as the drug or small molecule inhibits the transporter nucleic acid expression in the cells and tissues that express the protein. Experimental data as provided in FIG. 1 indicates expression in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, ovary fibrotheomas, and leukocytes.

[0184] The nucleic acid molecules are also useful for monitoring the effectiveness of modulating compounds on the expression or activity of the transporter gene in clinical trials or in a treatment regimen. Thus, the gene expression pattern can serve as a barometer for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. Accordingly, such monitoring would allow either increased administration of the compound or the administration of alternative compounds to which the patient has not become resistant. Similarly, if the level of nucleic acid expression falls below a desirable level, administration of the compound could be commensurately decreased.

[0185] The nucleic acid molecules are also useful in diagnostic assays for qualitative changes in transporter nucleic acid expression, and particularly in qualitative changes that lead to pathology. The nucleic acid molecules can be used to detect mutations in transporter genes and gene expression products such as mRNA. The nucleic acid molecules can be used as hybridization probes to detect naturally occurring genetic mutations in the transporter gene and thereby to determine whether a subject with the mutation is at risk for a disorder caused by the mutation. Mutations include deletion, addition, or substitution of one or more nucleotides in the gene, chromosomal rearrangement, such as inversion or, transposition, modification of genomic DNA, such as aberrant methylation patterns or changes in gene copy number, such as amplification. Detection of a mutated form of the transporter gene associated with a dysfunction provides a diagnostic tool for an active disease or susceptibility to disease when the disease results from overexpression, under expression, or altered expression of a transporter protein.

[0186] Individuals carrying mutations in the transporter gene can be detected at the nucleic acid level by a variety of techniques. FIG. 3 provides information on SNPs that have been found in the gene encoding the transporter protein of the present invention. SNPs were identified at 92 different nucleotide positions. SNPs such as these, particularly SNPs located 5′ of the ORF and in the first intron, may affect control/regulatory elements. The gene encoding the novel transporter protein of the present invention is located on a genome component that has been mapped to human chromosome 1. (as indicated in FIG. 3), which is supported by multiple lines of evidence, such as STS and BAC map data. Genomic DNA can be analyzed directly or can be amplified by using PCR prior to analysis. RNA or cDNA can be used in the same way. In some uses, detection of the mutation involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g. U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al., Science 241:1077-1080 (1988); and Nakazawa et al., PNAS91:360-364 (1994)), the latter of which can be particularly useful for detecting point, mutations in the gene (see Abravaya et al., Nucleic Acids Res. 23:675-682 (1995)). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g. genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers which specifically hybridize to a gene under conditions such that hybridization and amplification of the gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. Deletions and insertions can be detected by a change in size of the amplified product compared to the normal genotype. Point mutations can be identified by hybridizing amplified DNA to normal RNA or antisense DNA sequences.

[0187] Alternatively, mutations in a transporter gene can be directly identified, for example, by alterations in restriction enzyme digestion patterns determined by gel electrophoresis.

[0188] Further, sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature.

[0189] Sequence changes at specific locations can also be assessed by nuclease protection assays such as RNase and S1 protection or the chemical cleavage method. Furthermore, sequence differences between a mutant transporter gene and a wild-type gene can be determined by direct DNA sequencing. A variety of automated sequencing procedures can be utilized when performing the diagnostic assays (Naeve, C. W., (1995) Biotechniques 19:448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen et al., Adv. Chromatogr. 36:127-162 (1996); and Griffin et al., Appl. Biochem. Biotechnol. 38:147-159.(1993)).

[0190] Other methods for detecting mutations in the gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science 230:1242 (1985)); Cotton et al., PNAS 85:4397 (1988); Saleeba et al., Meth. Enzymol. 217:286-295.(1992)), electrophoretic mobility of mutant and wild type nucleic acid is compared (Orita et al., PNAS 86:2766(1989); Cotton et al., Mutat. Res. 285:125-144 (1993); and Hayashi et al., Genet. Anal. Tech. Appl. 9:73-79 (1992)), and movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (Myers et al., Nature 313495. (1985)). Examples of other techniques for detecting point mutations include selective oligonucleotide hybridization, selective amplification, and selective primer extension.

[0191] The nucleic acid molecules are also useful for testing an individual for a genotype that while not necessarily causing the disease, nevertheless affects the treatment modality. Thus, the nucleic acid molecules can be used to study the relationship between an individual's genotype and the individual's response to a compound used for treatment (pharmacogenomic relationship). Accordingly, the nucleic acid molecules described herein can be used to assess the mutation content of the transporter gene in an individual in order to select an appropriate compound or dosage regimen for treatment. FIG. 3 provides information on SNPs that have been found in the gene encoding the transporter protein of the present invention. SNPs were identified at 92 different nucleotide positions. SNPs such as these, particularly SNPs' located 5′ of the ORF and in the first intron, may affect control/regulatory elements.

[0192] Thus nucleic acid molecules displaying genetic variations that affect treatment provide a diagnostic target that can be used to tailor treatment in an individual. Accordingly, the production of recombinant cells and animals containing these polymorphisms allow effective clinical design of treatment compounds and dosage regimens.

[0193] The nucleic acid molecules are thus useful as antisense constructs to control transporter gene expression in cells, tissues, and organisms. A DNA antisense nucleic acid molecule is designed to be complementary to a region of the gene involved in transcription, preventing transcription and hence production of transporter protein. An antisense RNA or DNA nucleic acid molecule would hybridize to the mRNA and thus block translation of mRNA into transporter protein.

[0194] Alternatively, a class of antisense molecules can be used to inactivate mRNA in order to decrease expression of transporter nucleic acid. Accordingly, these molecules can treat a disorder characterized by abnormal or undesired transporter nucleic acid expression. This technique involves cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Possible regions include coding regions and particularly coding regions corresponding to the catalytic and other functional activities of the transporter protein, such as ligand binding.

[0195] The nucleic acid molecules also provide-vectors for gene therapy in patients containing cells that are aberrant in transporter gene expression. Thus, recombinant cells, which include the patient's cells that have been engineered ex vivo and returned to the patient, are introduced into an individual where the cells produce the desired transporter protein to treat the individual.

[0196] The invention also encompasses kits for detecting the presence of a transporter nucleic acid in a biological sample. Experimental data as provided in FIG. 1 indicates that the transporter proteins of the present invention are expressed in humans in placenta choriocarcinomas, retina, uterus leiomyosarcomas, breast, and ovary fibrotheomas, as indicated by virtual northern blot analysis. In addition, PCR-based tissue screening panels indicate expression in leukocytes. For example, the kit can comprise reagents such as a labeled or labelable nucleic acid or agent capable of detecting transporter nucleic acid in a biological sample; means for determining the amount of transporter nucleic acid in the sample; and means for comparing the amount of transporter nucleic acid in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect transporter protein mRNA or DNA.

[0197] Nucleic Acid Arrays

[0198] The present invention further provides nucleic acid detection kits, such as arrays or microarrays of nucleic acid molecules that are based on the sequence information provided in FIGS. 1 and 3 (SEQ. ID. NOS: 1 and 3).

[0199] As used herein “Arrays” or “Microarrays”, refers to an array of distinct polynucleotides or oligonucleotides synthesized on a substrate, such as paper, nylon or other type of membrane, filter, chip, glass slide, or any other suitable solid support. In one embodiment, the microarray is prepared and used according to the methods described in U.S. Pat. No. 5,837,832, Chee et al., PCT application WO95/11995. (Chee et al.), Lockhart, D. J. et al. (1996; Nat. Biotech. 14: 1675-1680) and Schena, M. et al. (1996; Proc. Natl. Acad. Sci. 93: 10614-10619), all of which are incorporated herein in their, entirety by reference. In other embodiments, such arrays are produced by the methods described by Brown et al., U.S. Pat. No. 5,807,522.

[0200] The microarray or detection kit is preferably composed of a large number of unique, single-stranded nucleic acid sequences, usually either synthetic antisense oligonucleotides or fragments of cDNAs, fixed to a solid support. The oligonucleotides are preferably about 6-60 nucleotides in length, more preferably 15-30 nucleotides in length, and most preferably about 20-25, nucleotides in length. For a certain type of microarray or detection kit, it may be preferable to use oligonucleotides that are only 7-20 nucleotides in length. The microarray or detection kit may contain oligonucleotides that cover the known 5′, or 3′, sequence, sequential oligonucleotides that cover the full length sequence; or unique oligonucleotides selected from particular areas along the length of the sequence. Polynucleotides used in the microarray or detection kit may be oligonucleotides that are specific to a gene or genes of interest.

[0201] In order to produce oligonucleotides to a known sequence for a microarray or detection kit, the gene(s) of interest (or an ORF identified from the contigs of the present invention) is typically examined using a computer algorithm which starts at the 5′ or at the 3′ end of the nucleotide sequence. Typical algorithms will then identify oligomers of defined length that are unique to the gene, have a GC content within a range suitable for hybridization, and lack predicted secondary structure that may interfere with hybridization. In certain situations it may be appropriate to use pairs of oligonucleotides on a microarray or detection kit. The “pairs”, will be identical, except for one nucleotide that preferably is located in the center of the sequence. The second oligonucleotide in the pair (mismatched by one) serves as a control. The number of oligonucleotide pairs may range from two to one million. The oligomers are synthesized at designated areas on a substrate using a light-directed chemical process. The substrate may be paper, nylon or other type of membrane, filter, chip, glass slide or any other suitable solid support.

[0202] In another aspect, an oligonucleotide may be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application WO95/251116 (Baldeschweiler et al.) which is incorporated herein in its entirety by reference. In another aspect, a “gridded” array analogous to a dot (or slot) blot may be used to arrange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536, 6144 or more oligonucleotides, or any other number between two and one million Which lends itself to the efficient use of commercially available instrumentation.

[0203] In order to conduct sample analysis using a microarray or detection kit, the RNA or DNA from a biological sample is made into hybridization probes. The mRNA is isolated, and cDNA is produced and used as a template to make antisense RNA (aRNA). The aRNA is amplified in the presence of fluorescent nucleotides, and labeled probes are incubated with the microarray or detection kit so that the probe sequences hybridize to complementary oligonucleotides of the microarray or, detection kit. Incubation conditions are adjusted so that hybridization occurs with precise complementary matches or with various degrees of less complementarity. After removal of nonhybridized probes, a scanner is used to determine the levels and patterns of fluorescence. The scanned images are examined to determine degree of complementarity and the relative abundance of each oligonucleotide sequence on the microarray or detection kit. The biological samples may be obtained from any bodily fluids (such as blood, urine, saliva, phlegm, gastric juices, etc.), cultured cells, biopsies, or other tissue preparations. A detection system may be used to measure the absence, presence, and amount of hybridization for all of the distinct sequences simultaneously. This data maybe used for large-scale correlation studies on the sequences, expression patterns, mutations, variants, or polymorphisms among samples.

[0204] Using such arrays, the present invention provides methods to identify the expression of the transporter proteins/peptides of the present invention. In detail, such methods comprise incubating a test sample with one or more nucleic acid molecules and assaying for binding of the nucleic acid molecule with components within the test sample. Such assays will typically involve arrays comprising many genes, at least one of which is a gene of the present invention and or alleles of the transporter gene of the present invention. FIG. 3 provides information on SNPs that have been found in the gene encoding the transporter protein of the present invention. SNPs were identified at 92 different nucleotide positions. SNPs such as these, particularly SNPs located 5′ of the ORF and in the first intron, may affect control/regulatory elements.

[0205] Conditions for incubating a nucleic acid molecule with a test sample vary. Incubation conditions depend on the format employed in the assay, the detection methods employed; and the type and nature of the nucleic acid molecule used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification or array assay formats can readily be adapted to employ the novel fragments of the Human genome disclosed herein. Examples of such assays can be found in Chard, T, An Introduction to Radioimmunoassay and Related Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986); Bullock, G. R. et al., Techniques in Immunocytochemistry, Academic Press, Orlando, Fla. Vol. 1 (1982), Vol. 2 (1983), Vol. 3 (1985); Tijssen, P., Practice and Theory of Enzyme Immunoassays Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1985).

[0206] The test samples of the present invention include cells, protein or membrane extracts of cells. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing nucleic acid extracts or of cells are well known in the art and can be readily be adapted in order to obtain a sample that is compatible with the system utilized.

[0207] In another embodiment of the present invention, kits are provided which contain the necessary reagents to carry out the assays of the present invention.

[0208] Specifically, the invention provides a compartmentalized kit to receive, in close confinement, one or more containers which comprises: (a) a first container comprising one of the nucleic acid molecules that can bind to a fragment of the Human genome disclosed herein; and (b) one or more other containers comprising one or more of the following: wash reagents, reagents capable of detecting presence of a bound nucleic acid.

[0209] In detail, a compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include small glass containers, plastic containers, strips of plastic, glass or paper, or arraying material such as silica. Such containers allows one to efficiently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another. Such containers will include a container which will accept the test sample, a container which contains the nucleic acid probe, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and containers which contain the reagents used to detect the bound probe. One skilled in the art will readily recognize that the previously unidentified transporter gene of the present invention can be routinely identified using the sequence information disclosed herein can be readily incorporated into one of the established kit formats which are well known in the art, particularly expression arrays.

[0210] Vectors/Host Cells

[0211] The invention also provides vectors containing the nucleic acid molecules described herein. The term “vector” refers to a vehicle, preferably a nucleic acid molecule, which can transport the nucleic acid molecules. When the vector is a nucleic acid molecule, the nucleic acid molecules are covalently linked to the vector nucleic acid. With this aspect of the invention, the vector includes a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, OR MAC.

[0212] A vector can be maintained in the host cell as an extrachromosomal element where it replicates and produces additional copies of the nucleic acid molecules. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the nucleic acid molecules when the host cell replicates.

[0213] The invention provides vectors for the maintenance (cloning vectors) or vectors for expression (expression vectors) of the nucleic acid molecules. The vectors can function in procaryotic or eukaryotic cells or in both (shuttle vectors).

[0214] Expression vectors contain cis-acting regulatory regions that are operably linked in the vector to the nucleic acid molecules such that transcription of the nucleic acid molecules is allowed in a host cell. The nucleic acid molecules can be introduced into the host cell with a separate nucleic acid molecule capable of affecting transcription. Thus, the second nucleic acid molecule may provide a trans-acting factor interacting with the cis-regulatory control region to allow transcription of the nucleic acid molecules from the vector. Alternatively, a trans-acting factor maybe supplied by the host cell. Finally, a trans-acting factor can be produced from the vector itself. It is understood, however, that in some embodiments, transcription and/or translation of the nucleic acid molecules can occur in a cell-free system.

[0215] The regulatory sequence to which the nucleic acid molecules described herein can be operably linked include promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage λ, the lac, TRP, and TAC promoters from E. coli, the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.

[0216] In addition to control regions that promote transcription, expression vectors may also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.

[0217] In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region a ribosome binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. The person of ordinary skill in the art would be aware of the numerous regulatory sequences that are useful in expression vectors. Such regulatory sequences are described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual. 2nd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1989).

[0218] A variety of expression vectors can be used to express a nucleic acid molecule. Such vectors include chromosomal, episomal, and virus-derived vectors, for example vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses, pseudorabies viruses, and retroviruses. Vectors may also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g. cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook et al., Molecular Cloning: A Laboratory Manual. 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1989).

[0219] The regulatory sequence may provide constitutive expression in one or more host cells (i.e. tissue specific) or may provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factor such as a hormone or other ligand. A variety of vectors providing for constitutive and inducible expression in prokaryotic and eukaryotic hosts are well known to those of ordinary skill in the art.

[0220] The nucleic acid molecules can be inserted into the vector nucleic acid by well-known methodology. Generally, the DNA sequence that will ultimately be expressed is joined to an expression vector by cleaving the DNA sequence and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known to those of ordinary skill in the art.

[0221] The vector containing the appropriate nucleic acid molecule can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial cells include, but are not limited to, E. coli, Streptomyces, and Salmonella typhimurium. Eukaryotic cells include, but are not limited to, yeast, insect cells such as Drosophila, animal cells such as COS and CHO cells, and plant cells.

[0222] As described herein, it may be desirable to express the peptide as a fusion protein. Accordingly, the invention provides fusion vectors that allow for the production of the peptides. Fusion vectors can increase the expression of a recombinant protein, increase the solubility of the recombinant protein, and aid in the purification of the protein by acting for example as a ligand for affinity purification. A proteolytic cleavage site may be introduced at the junction of the fusion moiety so that the desired peptide can ultimately be separated from the fusion moiety. Proteolytic enzymes include, but are not limited to, factor Xa, thrombin, and enterotransporter. Typical fusion expression vectors include pGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., Gene 69:301-315,(1988)) and pET 11d (Studier et al., Gene Expression Technology: Methods in Enzymology 185:60-89 (1990)).

[0223] Recombinant protein expression can be maximized in host bacteria by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein. (Gottesman, S., Gene Expression Technology: Methods in Enzymology. 185, Academic Press, San Diego, Calif. (1990) 119-128). Alternatively, the sequence of the nucleic acid molecule of interest can be altered to provide preferential codon usage for a specific host cell, for example E. coli. (Wada et al., Nucleic Acids Res. 20:2111-2118 (1992)).

[0224] The nucleic acid molecules can also be expressed by expression vectors that are operative in yeast. Examples of vectors for expression in yeast e.g., S. cerevisiae include pYepSec1. (Baldari, et al., EMBO J. 6:229-234(1987)), pMFa (Kjan et al., Cell 30:933-943(1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.).

[0225] The nucleic acid molecules can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf9 cells) include the pAc series (Smith et al., Mol. Cell Biol. 3:2156-2165.(1983)) and the pVL series (Lucklow et al., Virology 170:31-39.(1989)).

[0226] In certain embodiments of the invention, the nucleic acid molecules described herein are expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (Seed, B. Nature 329:840(1987)) and pMT2PC (Kaufman et al., EMBO J. 6:187-195 (1987)).

[0227] The expression vectors listed herein are provided by way of example only of the well-known vectors available to those of ordinary skill in the art that would be useful to express the nucleic acid molecules. The person of ordinary skill in the art would be aware of other vectors suitable for maintenance propagation or expression of the nucleic acid molecules described herein. These are found for example in Sambrook, J., Fritsh, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

[0228] The invention also encompasses vectors in which the nucleic acid sequences described herein are cloned into the vector in-reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to all, or to a portion, of the nucleic acid molecule sequences described herein, including both coding and non-coding regions. Expression of this antisense RNA is subject to each of the parameters described above in relation to expression of the sense RNA (regulatory sequences, constitutive or inducible expression, tissue-specific expression).

[0229] The invention also, relates to recombinant host cells containing the vectors described herein. Host cells therefore include prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.

[0230] The recombinant host cells are prepared by introducing the vector constructs described herein into the cells by techniques readily available to the person of ordinary skill in the art. These include, but are not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, and other techniques such as those found in Sambrook, et al. (Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989).

[0231] Host cells can contain more than one vector. Thus, different nucleotide sequences can be introduced on different vectors of the same cell. Similarly, the nucleic acid molecules can be introduced either alone or with other nucleic acid molecules that are not related to the nucleic acid molecules such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co-introduced or joined to the nucleic acid molecule vector.

[0232] In the case of bacteriophage and viral vectors, these can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. In the case in which viral replication is defective, replication will occur in host cells providing functions that complement the defects.

[0233] Vectors generally include selectable markers that enable the selection of the subpopulation of cells that contain the recombinant vector constructs. The marker can be contained in the same vector that contains the nucleic acid molecules described herein or may be on a separate vector. Markers include tetracycline or ampicillin-resistance genes for prokaryotic host cells and dihydrofolate reductase or neomycin resistance for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait will be effective.

[0234] While the mature proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of the appropriate regulatory sequences, cell free transcription and translation systems can also be used to produce these proteins using RNA derived from the DNA constructs described herein.

[0235] Where secretion of the peptide is desired, which is difficult to achieve with multi-transmembrane domain containing proteins such as transporters, appropriate secretion signals are incorporated into the vector. The signal sequence can be endogenous to the peptides or heterologous to these peptides.

[0236] Where the peptide is not secreted into the medium, which is typically the case with transporters, the protein can be isolated from the host cell by standard disruption procedures, including freeze thaw, sonication, mechanical disruption, use of lysing agents and the like. The peptide can then be recovered and purified by well-known purification methods including ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.

[0237] It is also understood that depending upon the host cell in recombinant production of the peptides described herein, the peptides can have various glycosylation patterns, depending upon the cell, or maybe non-glycosylated as when produced in bacteria. In addition, the peptides may include an initial modified methionine in some cases as a result of a host-mediated process.

[0238] Uses of Vectors and Host Cells

[0239] The recombinant host cells expressing the peptides described herein have a variety of uses. First, the cells are useful for producing a transporter protein or peptide that can be further purified to, produce desired amounts of transporter protein or fragments. Thus, host cells containing expression vectors are useful for peptide production.

[0240] Host cells are also useful for conducting cell-based assays involving the transporter protein or transporter protein fragments, such as those described above as well as other formats known in the art. Thus, a recombinant host cell expressing a native transporter protein is useful for assaying compounds that stimulate or inhibit transporter protein function.

[0241] Host cells are also useful for identifying transporter protein mutants in which these functions are affected. If the mutants naturally occur and give rise to a pathology, host cells containing the mutations are useful to assay compounds that have a desired effect on the mutant transporter protein (for example, stimulating or inhibiting function) which may not be indicated by their effect on the native transporter protein.

[0242] Genetically engineered host cells can be further used to produce non-human transgenic animals. A transgenic animal is preferably a mammal, for example a rodent, such as a rat or mouse, in which one or more of the cells of the animal include a transgene. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal in one or more cell types or tissues of the transgenic animal. These animals are useful for studying the function of a transporter protein and identifying and evaluating modulators of transporter protein activity. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, and amphibians.

[0243] A transgenic animal can be produced by introducing nucleic acid into the male pronuclei of a fertilized oocyte, e.g., by microinjection, retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Any of the transporter protein nucleotide sequences can be introduced as a transgene into the genome of a non-human animal, such as a mouse.

[0244] Any of the regulatory or other sequences useful in expression vectors can form part of the transgenic sequence. This includes intronic sequences and polyadenylation signals, if not already included. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the transporter protein to particular cells.

[0245] Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al., U.S. Pat. No. 4,873,191 by Wagner et al. and in Hogan, B., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of transgenic mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene can further be bred to other transgenic animals carrying other transgenes. A transgenic animal also includes animals in which the entire animal or tissues in the animal have been produced using the homologously recombinant host cells described herein.

[0246] In another embodiment, transgenic non-human animals can be produced which contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, see, e.g., Lakso et al. PNAS 89:6232-6236 (1992). Another example of a recombinase system is the FLP recombinase system of S. cerevisiae (O'Gorman et al. Science 251:1351-1355. (1991). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein is required. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

[0247] Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, I. et al. Nature 385:810-813 (1997) and PCT International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell, e.g., a somatic cell, from the transgenic animal can be isolated and induced to exit the growth cycle and enter G_(o) phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to pseudopregnant female foster animal. The offspring born of this female foster animal will be a clone of the animal from which the cell, e.g., the somatic cell, is isolated.

[0248] Transgenic animals containing recombinant cells that express the peptides described herein are useful to conduct the assays described herein in an in vivo context. Accordingly, the various physiological factors that are present in vivo and that could effect ligand binding, transporter protein activation, and signal transduction, may not be evident from in vitro cell-free or cell-based assays. Accordingly, it is useful to provide non-human transgenic animals to assay in vivo transporter protein function, including ligand interaction, the effect of specific mutant transporter proteins on transporter protein function and ligand interaction and the effect of chimeric transporter proteins. It is also possible to assess the effect of null mutations, that is mutations that substantially or completely eliminate one or more transporter protein functions.

[0249] All publications and patents mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention which are obvious to those skilled in the field of molecular biology or related fields are intended to be within the scope of the following claims.

1 126 1 2673 DNA Homo sapiens 1 ccgcaacccc gacggcgccc caaacgctgt tgcgccgcgc gccccgccca gcccggcctc 60 gcgctggtcc cggtctcgcc ccgcagccct cgatctcccg tgacttcctc ggccaggccg 120 cctgcgcctc tgggaccatg ttgcgctggc tgcgggactt cgcgctgccc accgcggcct 180 gccaggacgc ggagcagccg acgcgctacg agaccctctt ccaggcactg gaccgcaatg 240 gggacggagt ggtggacatc ggcgagctgc aggaggggct caggaacctg ggcatccctc 300 tgggccagga cgccgaggag aaaattttta ctactggaga tgtcaacaaa gatgggaagc 360 tggattttga agaatttatg aagtacctta aagaccatga gaagaaaatg aaattggcat 420 ttaagagttt agacaaaaat aatgatggaa aaattgaggc ttcagaaatt gtccagtctc 480 tccagacact gggtctgact atttctgaac aacaagcaga gttgattctt caaagcattg 540 atgttgatgg gacaatgaca gtggactgga atgaatggag agactacttc ttatttaatc 600 ctgttacaga cattgaggaa attatccgtt tctggaaaca ttctacagga attgacatag 660 gggatagctt aactattcca gatgaattca cggaagacga aaaaaaatcc ggacaatggt 720 ggaggcagct tttggcagga ggcattgctg gtgctgtctc tcgaacaagc actgcccctt 780 tggaccgtct gaaaatcatg atgcaggttc acggttcaaa atcagacaaa atgaacatat 840 ttggtggctt tcgacagatg gtaaaagaag gaggtatccg ctcgctttgg aggggaaatg 900 gtacaaacgt catcaaaatt gctcctgaga cagctgttaa attctgggca tatgaacagt 960 acaagaagtt acttactgaa gaaggacaaa aaataggaac atttgagaga tttatttctg 1020 gttccatggc tggagcaact gcacagactt ttatatatcc aatggaggtt atgaaaacca 1080 ggctggctgt aggcaaaact gggcagtact ctggaatata tgattgtgcc aagaagattt 1140 tgaaacatga aggcttggga gctttttaca aaggctatgt tcccaattta ttaggtatca 1200 taccttatgc aggcatagat cttgctgtgt atgagctctt gaagtcctat tggctggata 1260 attttgcaaa agattctgta aaccctggag tcatggtgtt gctgggatgc ggtgccttat 1320 ccagcacctg tggtcagctg gccagctacc cattggcttt ggtgagaact cgcatgcagg 1380 ctcaagccat gttagaaggt tccccacagc tgaatatggt tggcctcttt cgacgaatta 1440 tttccaaaga aggaatacca ggactttaca gaggcatcac cccaaacttc atgaaggtgc 1500 tccctgctgt aggcatcagt tatgtggttt atgaaaatat gaagcaaact ttaggagtaa 1560 cccagaaatg atgttgcatt ttttgcttta gcctgataat tgaaactttc aacaatctct 1620 ggagtgactt tttctcctcg aattgaaaca agtctatggc aaaagaagct gcattttttt 1680 cacaaaaggg aagacggtaa caatggtcac ttcaaacttt tgggctaaat tatatgtaca 1740 cagaaatgtt caaaatcata gttttaatgt gttttgaaaa ggccacacaa ttatacttta 1800 tcttttctta ataatcctgc aaatctctgc cctgaatccg aaatctgaaa atgtactggc 1860 ttgaacaaaa tttgttttgt gtgttagagt tataaatcat taatctttat ttcgggtggt 1920 ttacgtttat gccagttcct ttatatttaa atttcttgtt ttatatattt tgaatgtctt 1980 tatagatttc tttaaatttc cttatagaac cattaataga aaatcattac atttaaaata 2040 taccttacag caaaagcatc caaataagta tagggtttat gtccttattt ttctttcagc 2100 tgaatacgaa tgaacacagt ggtggaattt ctgaagggaa gtgatgaaat tatatttatt 2160 tcagtgggca cttttccatt ttaccactgt accattattt ggttcctgga gttatacact 2220 aattttcagt atattactgt taaattacca acacaaggca atttatttga aagattccgt 2280 ttatcctgcc attgctttga aaagcagcag gaaacgaaat tttttgactt gtatcagctt 2340 ctgcagagca tctttgtttt cctttgtcct ttgtttccta ccttttgaat cagattccgt 2400 tttagtcagg aagacttctt gggaccattc ttagtaacct gaaatttctt ttttaattgc 2460 atgaagtgga ttgatcatga gcaagtgatg ggctttattt ctccctcact ggtgaatatc 2520 ctttgaactt gctgtttgca atatgggcag ccacaaaggg ggagagatgc ctattaaatc 2580 ggcggggtgt atgacttctg aaaacattgg ataccctatt ttgaaaaggg aaaggcccaa 2640 tttggggaaa catataccaa tgcatgattt ctg 2673 2 477 PRT Homo sapiens 2 Met Leu Arg Trp Leu Arg Asp Phe Ala Leu Pro Thr Ala Ala Cys Gln 1 5 10 15 Asp Ala Glu Gln Pro Thr Arg Tyr Glu Thr Leu Phe Gln Ala Leu Asp 20 25 30 Arg Asn Gly Asp Gly Val Val Asp Ile Gly Glu Leu Gln Glu Gly Leu 35 40 45 Arg Asn Leu Gly Ile Pro Leu Gly Gln Asp Ala Glu Glu Lys Ile Phe 50 55 60 Thr Thr Gly Asp Val Asn Lys Asp Gly Lys Leu Asp Phe Glu Glu Phe 65 70 75 80 Met Lys Tyr Leu Lys Asp His Glu Lys Lys Met Lys Leu Ala Phe Lys 85 90 95 Ser Leu Asp Lys Asn Asn Asp Gly Lys Ile Glu Ala Ser Glu Ile Val 100 105 110 Gln Ser Leu Gln Thr Leu Gly Leu Thr Ile Ser Glu Gln Gln Ala Glu 115 120 125 Leu Ile Leu Gln Ser Ile Asp Val Asp Gly Thr Met Thr Val Asp Trp 130 135 140 Asn Glu Trp Arg Asp Tyr Phe Leu Phe Asn Pro Val Thr Asp Ile Glu 145 150 155 160 Glu Ile Ile Arg Phe Trp Lys His Ser Thr Gly Ile Asp Ile Gly Asp 165 170 175 Ser Leu Thr Ile Pro Asp Glu Phe Thr Glu Asp Glu Lys Lys Ser Gly 180 185 190 Gln Trp Trp Arg Gln Leu Leu Ala Gly Gly Ile Ala Gly Ala Val Ser 195 200 205 Arg Thr Ser Thr Ala Pro Leu Asp Arg Leu Lys Ile Met Met Gln Val 210 215 220 His Gly Ser Lys Ser Asp Lys Met Asn Ile Phe Gly Gly Phe Arg Gln 225 230 235 240 Met Val Lys Glu Gly Gly Ile Arg Ser Leu Trp Arg Gly Asn Gly Thr 245 250 255 Asn Val Ile Lys Ile Ala Pro Glu Thr Ala Val Lys Phe Trp Ala Tyr 260 265 270 Glu Gln Tyr Lys Lys Leu Leu Thr Glu Glu Gly Gln Lys Ile Gly Thr 275 280 285 Phe Glu Arg Phe Ile Ser Gly Ser Met Ala Gly Ala Thr Ala Gln Thr 290 295 300 Phe Ile Tyr Pro Met Glu Val Met Lys Thr Arg Leu Ala Val Gly Lys 305 310 315 320 Thr Gly Gln Tyr Ser Gly Ile Tyr Asp Cys Ala Lys Lys Ile Leu Lys 325 330 335 His Glu Gly Leu Gly Ala Phe Tyr Lys Gly Tyr Val Pro Asn Leu Leu 340 345 350 Gly Ile Ile Pro Tyr Ala Gly Ile Asp Leu Ala Val Tyr Glu Leu Leu 355 360 365 Lys Ser Tyr Trp Leu Asp Asn Phe Ala Lys Asp Ser Val Asn Pro Gly 370 375 380 Val Met Val Leu Leu Gly Cys Gly Ala Leu Ser Ser Thr Cys Gly Gln 385 390 395 400 Leu Ala Ser Tyr Pro Leu Ala Leu Val Arg Thr Arg Met Gln Ala Gln 405 410 415 Ala Met Leu Glu Gly Ser Pro Gln Leu Asn Met Val Gly Leu Phe Arg 420 425 430 Arg Ile Ile Ser Lys Glu Gly Ile Pro Gly Leu Tyr Arg Gly Ile Thr 435 440 445 Pro Asn Phe Met Lys Val Leu Pro Ala Val Gly Ile Ser Tyr Val Val 450 455 460 Tyr Glu Asn Met Lys Gln Thr Leu Gly Val Thr Gln Lys 465 470 475 3 69327 DNA Homo sapiens misc_feature (1)...(69327) n = A,T,C or G 3 aacccatgtt agtgtgcagt tctgctggca cacacatgca gttgtgtaac cactaccacc 60 aaaagcaaga tgtaaaatag ctccatcacc cccacaagcc ttctgatgct cttttgtcat 120 caattccctt cccgctagtc acaactggta actactgatt tgttttctgt ccctatagtt 180 ttgccttttc cagaatgtca ttgttgacag gtatcagtaa ttcattcctt tttattgcta 240 attactatct cactgtatga atgcaacaca ggttgtttac cagttcaccc gttaaagaac 300 attttgtttc tgcgcttgac agttatgaat agaactgcta taaaccctca agtaaaagtt 360 ttggtgtgaa gataattttc tcagcaaaaa cgctgacagg taatttttct aagtattact 420 tttttaaaaa agtaaaatag cctgtagccc cagctactca ggaggctgag gcaggagaat 480 agcttgaacc caggaggcgg aggttgcagt gagttgagat tgtgccactg cattccagcc 540 tgggcgacag agctagactg tctcaaagaa aaaaaaaaaa aataacaaat aaataaaaag 600 taaaatgaaa gcatgtaagt gtaagatgac tagttcaagc aacctctctt caagtacaga 660 gtattcagag tagagattaa aagaggtttt caaggacaga gaaaatttga agtttgaagg 720 cagttccaaa ggaaggcaat gattcttaat aagactggaa gttggaagta atataaaaag 780 ataaatcagt ttcaagatga ttttactaag caggcagccc ttaatttaca aattctagat 840 tcatacatat cttaaacata caaaatgata tgaggagagg taagttcagg gtctgagttc 900 ctggctgttg ttggaactga tttctgtgta gtgattcaga agatgtgaga caccctaatt 960 tacaagtaca gaggtatctt cttttctgca aacagcagta caacaatagt tcctcttacg 1020 cagctgtgaa tgaacaggat tattacaatt aatgatatct catttgattg gcgccttaga 1080 gaattaagac ctttcacacc taatatacaa ctttgttgtg aaggcagata tttatattct 1140 cattttactg atgagagact acccggagac gctatgtcac acctgaagga ttaggtactt 1200 tctctgttaa gtccaatgtt ccttccgtta ttccatgcta ggcagtaata agttctgtct 1260 tgcctgagta ataagctcca aacctcggaa ctgcacccat cttgagaagg aggagggcgc 1320 tgtggttttt tctgataagt gcagctggca gacactctat acgcttaatc acgggcaaat 1380 cctacctaag ctgcctacca aactagtcct tcttttcccc gttgcccacg cagatggctg 1440 ttgatctttt ctgcaacaaa tccaggagtt tctccttttt gttttataat tgctccaata 1500 gatgctttag gatttaactc tctgcttttt aaagcagaat cgccatccca ggtgtgcaac 1560 cacgaaaaaa ttagacatcc gtgagagaca atgccctcca tggcccagtt tccaggcaga 1620 gagaagcagc tctgggctga ccgccaaggc tccggcccga gagggtcttt aagtggagta 1680 accagtcttc aagaccccgc tcccaagcca ccgacgcgct gacgctgcag ccctggacct 1740 gctgggggcc tcttcctcgg acccgcatgc tgacagcggg actggcaact gggcagaggt 1800 cgaccccggg tccgcacagc acctcccgag acccagctcc cagctccctc acttccggct 1860 ctctggaggc gggcccggcc agtgccgccg aggccagcgc ggcgagctcc tccccagcag 1920 cggcgggacg gccacaccct gcgcgccgcg cgggctcggg tggggtctcc gctcctgcgc 1980 cctgcgcgcc gcagccgcac ccccgacggc gccccaaacg ctgttgcgcc gcgcgccccg 2040 cccagcccgg cctcgcgctg gtcccggtct cgccccgcag ccctcgatct cccgtgactt 2100 cctcggccag gccgcctgcg cctctgggac catgttgcgc tggctgcggg acttcgtgct 2160 gcccaccgcg gcctgccagg acgcggagca gccgacgcgc tacgagaccc tcttccaggc 2220 actggaccgc aatggggacg gagtggtgga catcggcgag ctgcaggagg ggctcaggaa 2280 cctgggcatc cctctgggcc aggacgccga ggaggtgggt cgccgccggg gcgccgcctg 2340 agcgtaggga gggctgcggg cgctggggac actgcgagga ccgaggaggg cggcggcttg 2400 aggcgttgcc aggagaggaa ggaggaactg tggcgcccag cgctccggtg gcttcagaaa 2460 ctcgggcgtg gggccgcgac cggcgacccc ggtaacagaa gtgggtcata atacgaaagt 2520 ctactggtat ttgtccagat aaaatgagtg ttgtggacac tctggcccac gggcactgtt 2580 aaatttttaa gacacttttg tcctgaatcc atcccaggtt ctttgttttc tgttttaata 2640 ccttgcagac atgtaatccg ttttagctgt cagacttcag tgggtcccaa gttttgtata 2700 aaggcgcaca cattcgatct ctttcgaagc tgctttgtta cagcagctat gtgtattgtc 2760 tactgtttga aaactgtttg aaaaccaatc gcgtgtttcc cccacttcct gttgagaagg 2820 aatggcggca ttccattgtt taagacattc ctaggttaat gccctaggta cataaattga 2880 tctgaagggt tgacttgacc tgcgactgag caatttcatt ttctctgagt catcttaact 2940 gtgcccctga acttctgccc ctttagtagg gtggagatat gtggaacttc tccaaccctg 3000 ttgaagcgtt ccctgacact ggcattctct tatccaaaga gggaaagtga ttaggttact 3060 atgagggcca acaactgtta tatagttata tttcacttct cttttaatgt ctttggtagt 3120 tataggcctc ttcagtttac tgtttcttct agagtcagat ttagtaagtt acaatttttt 3180 ttgaaactgc ctgttctgtc caaggttcat aatactcacc gatgatttta taacacttct 3240 gactgaatct gtaggtaggt tctctatttc attcctcata tctatccttt tctccccttc 3300 aatcttgcca aagttttgtg tattttattc atactttgaa ggaaccaact tttggtactt 3360 tgtgctgatt gtcccagaaa tggcccagtt ggagttcccc accatgtcca atcattggct 3420 ggaagcagcc caggaaaggg acgaccttgc tgcagtgcat cagcagatgc cagggttaga 3480 ggctagagag tggaagtcaa ctgtgttcct cacagtaggt gcctttgaag ggagatctca 3540 gtggtacaac tccatggtcc ctacaatata caaaagctct ttggagtgct caatgatttt 3600 taagattgta aagggatcct gagatcaaaa agcttgagaa ttgctgctgt atcaccattt 3660 ttacgtaact gcatcatatt ctgttatatg tttgtgtcat agtatatgtt accaattctt 3720 tttaaatcac cttttacttt attgatagtt taaaaacgat tgtaagtgaa attgcaatgg 3780 atgtcctttg tattcatttt ctcattctgg tccagttact ttcgtaggat aaattttgag 3840 gagtggacat tgctgagtct gaaggtaaca cacattttaa actgggatac gtattgcctt 3900 tcggaaacct tagacccatt ttcactcttt tgactgacag tgcttgcttc tccacatcct 3960 cgctcattca gggtatcagt ctttgtaaag tctcctattc tgcaggtgaa attccttttc 4020 atttcctgtc ttagtccatt tagtgttgct atagtggaat atctgagaca gggtaattta 4080 taaagaaaag acatttattt agctcacagt tccgcaggct gggaagttta agaagcgtgg 4140 tgctggcatc tgctggactc ctggggaggg ctttcctgct gtgtcacaac atggtggaaa 4200 gtcaaagtgg aagtggacat gtgtgaagaa gcaaaatccg aggggtgtcc tggctttata 4260 gcaacccagc ctcgagggaa ctgatccatt actgagggaa ctaattcagt ctcatgagag 4320 agagaactca ctcactactg caagaatgac accaagccat tcatgaggga tctgcctccg 4380 taaccctgac acctcctgct aggtccctcc tcccaacacg gccacatcag ggatcagact 4440 tcaacatgag tttttgtggg gacaaacaaa acgtagcact tgctttgcct tttggttcta 4500 ttcacatcct ccacaggatt gcattatgcc tacccatttg gtgagggcag tcttctttaa 4560 ttggtttact gattcaaatg ctaccctcct ccagagacat cctcacagac acacccagaa 4620 atcatgtttt accagttatc tgggcatccc ttagtccaga cgagttgata cataaaatta 4680 accatcacac atgggataga attaggatta cacagtcaac ctttatggga gaaaatttca 4740 gaggcatgtc aggggtttat gtaatgtcaa ggagtgagga cattggctac ttgagcatag 4800 aaatgagaac tgtggggtga ctcttcggtg gaaagtttca aggtagtagt ttgtatctaa 4860 gccaaatact cagcttgaag caaaatctct ataaattttc atctgatttg atctcatctc 4920 cgtgtttcca agcatttgta atgaattgag catttagaag agaacaaatt tctgtttaag 4980 tttctttaga ttttagatgg aaagaatgta gaaataagag tagaatgtag aaataggtat 5040 aaagaatata atagctaacc attactaagt gttccagaat tatccaggga agagaaaaga 5100 attcaaggca agtcctgaga caaaattaag aaccaattgg aagtgaaagc gctacatttt 5160 ttttttctgg tatgaccttt cttttctata tgttccaaat ctcctcacta tgaaattagt 5220 gaaaaattaa agttaaaaat tagagaaaat tcacattaag ttctcctagg actcagtagt 5280 ataagggtat agactgagag tagaatgtag tgtgagaaca aggagataca gtatttaacc 5340 attactaatt ctcttatact tgtctagtaa tcctatttcc ttttaaaagt cttcagttat 5400 tttctcttta cgcacctcct tctccctctt gtcttcctcc ttctaccccc atctttcttc 5460 ctgtggagcc ttcatgaatg ggattagtgc ttgtataaaa gtgacctgga agaccttcct 5520 tgccccttcc accatgtgag gacacagtga gaaaacagtg gtccatggaa ccggaaagtg 5580 ggtcctcact agacagtaaa tctcctagca cttcgatcta ggacttccag tgtctggaac 5640 tgcaagaaat caatgcttat tgtttaagta agccagtagt atttttgtca tagcagccca 5700 gttggactag gacaattacc aagagcaaga agggaagcag caagctacaa gagagttccg 5760 tccttggtgt aaattgaccg tgtaatcctt gtcaagtttg agccttactg gagctttact 5820 ttcttattct taaaatgcag atatcttgcc tgcatcctgg acagagcttt taacaaggtc 5880 atatgttgca gaatatgaaa gttcatgtta aaaaaccctt taaaatgtgg tatcccattt 5940 actagctggt gaacttcttg aggaacctct gtgcccatgg gtatgaagtg tatgctgaat 6000 gatcacccaa tgttagagga gtgggtggac tggtaacctg atttaagggc cattctaact 6060 cttacattct atgatttttt taattctgtc tttaagtttt tacatttaca atcacagaaa 6120 aaatagtcac atagaagaat agtagcttag caaatgttta ttgcattgag tggaatcagg 6180 atttcactcc attaagtaat tcctctgtta acaaagaggg ttcatttcat ttttatttca 6240 ttaatattgc tttttttttt ttttttctgg agacagaatc ttgctctatc accaaggctg 6300 gagtgcagtg gtgcgatctc ggctcactgc agcctctgct tcctggattc aagcgattct 6360 tgtgcctcag cctcccaagc agctgagatt acaggcacat gccaccacac ctggttaact 6420 tttgtatttt ctagtagaga tgggattttg ccatgttggt caggctggtc ttgaattcct 6480 ggcctctagt gatctgcctg cctctgcctc tgaaagtgct aagattacag gcatgagcta 6540 ccatggccag cccatttcct taatatttta attgtcagac atgttatggt ttctggcaca 6600 atattaagaa gacatgatat gaaatcacag ggtgaatttt agggcatcac aacagaaaga 6660 ttatggtata agaaaaacaa tggaattcca actacatttc tgtcaaatgt tctaaaatat 6720 ataaaatctg tatcttttgt gttctctcct gatttatatt ctaaatttga tgttatcctt 6780 ctctgcagaa ataaagtgtc tgaaagaatg aaaaaaatgg aagaattctt tagtaaggta 6840 taaaataccc tttctatctt tgtagcattc taagcctttt gtcacctttc caaactccca 6900 acatgccata ttccctgact aggccacagc catgtacatt gatcccttta ttttcttctc 6960 tctgcctgag atttctctca ttcccccttc tctgcctggt atatgattgc ccattgttta 7020 aggccccaac tcacctttat aatcttccta gcccactttc tttatcggta ttccagaaaa 7080 aacaaaagaa gcttccacaa gacaacattc tgtaatacac tgcttaactt cttttgaccc 7140 tgctgagttc aaaaatctta tctttttaag gattgaatgg agtccaccaa ggtatctata 7200 tttgacagga tttatgaaaa caaaaggatt tgttgagaaa gtttgaagcc taactctgaa 7260 acgtggatca tagtgtttac tacacattaa ctgttttagt ggatgtaata gttattatta 7320 taggctgtgg aatcagaaca gggttcaaat gttttcaccg cttgctagac tgtggccttg 7380 ggcatgttat ttaatgcctg gaggcctcaa atgttaacta ggaatggtaa gacctaccca 7440 gtaacttagc ataaatagta aattcattca tttaatgttt tcaaacagtg ccagacattg 7500 tttaatgaac tggggatata gtggtgaaca acactgacag cgttcttcat tgtattctca 7560 aaaccctccc tatagtaagt aggtctgtgt gtgtgtgtag gtgcatgggg aataaaaaat 7620 aataagcaaa taatgaacag ggtaatttca aaaagcagaa agagctattc aacaaaacta 7680 cctgcctttt attagatgaa actctcaact ctatggtttg ttctctcctg tcaattctgt 7740 taaatgctgt cagcctgttt tccttatcac cctggccacg acttctgtct tttctgcttg 7800 gtcctgtaga ctctaaccca aggctcattc tctgcctggc tatctgcctt ctgtggctct 7860 ttgccactac ctacattttc tgtgttgcac agggaaggac cattccctgt ggaccataaa 7920 attctctttt tgaaagaatt cattcttgat tgggccacag cacatcttgt gaaacagcat 7980 tagacatttg ccactgctca gcagctctgg gggaaaatgt ttactgagaa gcgtacagta 8040 gtttttttga ctaaccatgg tgcaacctcc tcccagaggg aaacctatga gtatttcaag 8100 gacatgtgat ggtctgtttt tgtccccagt atctgacatg atgggtagtg tagagcaaga 8160 gcttacagat aatggctaaa ttaaattttc tttttgaatt ttaatattca actttttagg 8220 gtacccaatc tccatattta ggaaaataaa ttacataaaa agtggagagt ttttattgtg 8280 aaactgcacc tccatattcc cagtggtgca ggatgaggga gcacaggtgt tggtctgggg 8340 aagccagggc cctctgtggt tctggagggt gaggattaag aggaagcctt agatagtatt 8400 tatgagtatc tgctgacttc tctctgggac ccaagatcac tgaacttttg cctattttga 8460 gatcatcttt ccaatccagc cactaacagc tgaaggatag gcttgccctg gagccattgt 8520 agtggttgga tgaagataaa agataaaaaa ctgtgagggg aggtgtcaca gaagaaaggg 8580 cccatgtggg cagattttca ttcaattcct agtctttatt acagcaattc tccagtgctg 8640 caaccttaga aaaggattcc tacaacacaa tgtaggtacc catcagcagc agattggata 8700 aagaaaatgt ggtacataca caccatggaa tactatgcag ccataaaaaa ggagcaaaat 8760 catgtccttt gcagcaatat gaatgcagct ggaagccaat aacttaaacg aattattgta 8820 gaaacagaaa aacaaatact gtgttctcat ttacaggggg agctaaacct tgggtaaatg 8880 gggcataaag atgggaacaa tagacactag ggactccaaa aggggggagg gagggaggag 8940 ggcaagggct ggaaagcttc ctactgggta ctttgttcac aacctgggtg atggcacgat 9000 taggagctca aaccccagta tcacacagta tacccttgta acaagctgat ggtgtaaccc 9060 ctgaatctac aataaaatta ttttatttta aaaaatcatt ataaggattt ttaaaaagaa 9120 ggattcctag acaggtgcag ccaaacaatt ttttttaaat gttggcaggc cgccaccgcc 9180 agtcacttat gctgcaatag cccatgtccc aacattccca acctacttct ctccaaaaga 9240 gaagctatac tttcagatgg ccctgtgctg ggttctccct ggaagtttct ggggaaaggg 9300 gcttgagttg ccccgactgg actcttcctg gagtgggagc cggggcttct gatcagacgt 9360 gagtgaggca ggaactccgc ggtctcccag cgcagcccag agtgcggtcc cacgcaggtc 9420 ccgggtcctg cgcgctcgcg cctttgcgct gaagccgtta ggatgagccc tctccttcca 9480 gagctttaac cgatgaaggt gcattgtgtt tggcgcccct gaggaggatg ctgtcttagg 9540 cctcttccca ctggacgtgt gtggtgggca gagatcccgt tcgtcggtcg cacttccacc 9600 ccgctggggc tcactcaggc cgcggagctg cgagggagac atcctcgatg gactccctct 9660 acggagatct cttttggtac ctggactata acaaggatgg gaccttggac atttttgagc 9720 ttcaggaagg cctggaggat gtaggggcca ttcaatctct agaggaagcg aaggtgggtc 9780 tcactggggc tgtaatcaga gagacgttgg ggctgggagc cctggagagg cattgggcag 9840 agagggcaaa atttacatgt tgtcaagctt gacctgggcc cactgcagtg ttcaggtggt 9900 tgaccagcgt taccgtttat taagaataac aacacagcta acacatttct caagtatttt 9960 tctccgtttt ctccttggct gtagtaaaat ctccaacttc agattgctct caagatgttg 10020 gctacataca gccttgtctt aggagtcacc ttgttcaatg tgctcacctg tcattagtca 10080 cccagagggg cgtctaggct aaagatgcgc cctccccagt tcagagaact ggaataatca 10140 ctctacgtgt atttgggagt ggggtggtga ttggaaattt tctgatgtta tgttttggtt 10200 tctgttcctg gaagggggca gtggaagtgg cttttactct cgggtttcac tagtgctgag 10260 gtttcctcat aatatgcctt aattgataga ccctagttat cagtaccgag cttaggctaa 10320 cccttctctt ccccagaagg ctaacctaca ggctccttct cagcatgttg tgcttcgtac 10380 atactcctat tgcagtattt ccaagtcatt tttcatttgg aatttattat tgtatataat 10440 aattacttta taagtatatt tgctctttgg atgtttgacc cggtagactg ggagatcatg 10500 agcatgtgga ctattgagtt tattttggat aattggtact tcgtgcccaa aaaactgtca 10560 gttgagttct gtcatgttga aatttagtaa aactctttct attagccatg tgaactttgg 10620 gaatattgaa gcatccattc agtcatgggt cagttctagt ttgagcacat tctatattcc 10680 aagccccata ccctggtatc ctcatctgtt atatcagagg cctggactgt gtactttctg 10740 tggaccaatt cagtccaaaa tgttatttct gcaaagctta tctggatttt taattcctag 10800 aaaaaagcag tgtttctcct tttaaagtta agtgttcttg ttcaggtgca gtggctcatg 10860 cctgtaattc cagcactttg ggaggccaag gcaggtggat cacttggggt caggagttca 10920 agaccagcct ggccaatatg gtaaaacccc atctctacta aaaatgcaaa aattaaccgg 10980 gtgtggtggt gggtgtgtgt agtcccagga ggctgaggca ggagaatcac ttgagcctgg 11040 gaggcagagg ttgcagcaag ctgagattgc atcactgcac tccaacctgg gtgacagagt 11100 gagactccat ctcaaaaaga aaaaaaaaaa gttaagtgtt cttcatattt gtttaaagac 11160 actcttatat ttagatttgc aagtgtaagt tgtatttgtt tatttgatac aaactagcct 11220 ttcataagaa attctgggtt agctatcaag tcgaatcttt tgaaacacat ttcttcctta 11280 ttgaaacaaa aggtttgtag agctgtcttg catttttggc aaggacgctt tgtgtaccta 11340 gtggtgactg aggagggttc acatgtcaaa acccaaggga ggggtgtccc cagagaattc 11400 tgcaccaacc acacagaaca ttctgtttca gaggagcacc attgtgactt ttcctcaagt 11460 ggcagtcaca tcgttaggag gttttgatgt gaggtctctt cccacacgtc tccacctccc 11520 cagtaggaaa atttgtttat atagacaaaa ctcaactgat taaaaaaaaa aaaaagaaat 11580 gatacttaca ttgtcgtgtt aagatacaaa agcaataact ttttattgtg aaaatagtct 11640 gtttttgaac aatatattgt tttgtttttt cctgtgaaag ttgagaaact aaatatacga 11700 agagataatg gtcagaccat aaataaaaat agaactttga ctcaaaattt acagcagtct 11760 gcccagaaaa ccagcccttt atctaaaata aacagaccag gaaaccagcc tgttatgtca 11820 gacttatagg aagtcaggtt gctatctcta gagacaatac acaaagctat gcaataactg 11880 ctgtaacagc cccaaatggt cagaatttga ttaataaccg acagcccccc taattttttt 11940 cttcactnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnttc 12000 accgcttgct agaactgtgg ccttgggtca tgttatttaa tgcctggagg cctcaaatgt 12060 taactaggta atggtaagac ctacccagta acttagcata aatagtaaat tcattcattt 12120 aatgttttca aacagtgcca gacattgttt aatgaactgg ggatatagtg gtgaacaaca 12180 ctgacagcgt tcttcattgt attctcaaaa ccctccctat agtaagtagg tctgtgtgtg 12240 tgtgtaggtg catggggaat aaaaaataat aagcaaataa tgaacaataa aattatttta 12300 tttaaaaaaa aagaaatgat acttacattg tcgtgttaag atacaaaagc aataactttt 12360 tattgtgaaa atagtctgtt tttgaacaat atattgtttt gttttttcct gtgaaagttg 12420 agaaactaaa tatacgaaga gataatggtc agaccataaa taaaaataga actttgactc 12480 aaaatttaca gcagtctgcc cagaaaacca gccctttatc taaaataaac agaccaggaa 12540 accagcctgt tatgtcagac ttataggaag tcaggttgct atctctagag acaatacaca 12600 aagctatgca ataactgctg taacagcccc aaatggtcag aatttgatta ataaccgaca 12660 gcccccctaa tttttttctt cacttccaac ttaggacgaa ccagagaaag ctaaatatgc 12720 accacctact aatcaaatag ggtgccgcgt ttctaatgaa ccctcctaca gcttccccag 12780 gccagcagcc cccaatcagg aaacgcctga agccttccct ttttctcact gtaaagcttt 12840 cccactcctc tgcctggctt tgagtctctg tcaatacaca agtgagggtg tctgactccc 12900 ttgctatagc aaactcgggc caagtagatt ttacttttct catttgattg gtcttttatt 12960 tctagaagga acatacaaga aaatttaaag gggaatccat tcctaatctt tcatattata 13020 gtagtcccct tttatctgca gggcatattt tccaagaccc ccactgaata cctgaaactg 13080 tgggtaatat tgaaccctat atatactctc tctatatata catatatata tatatttttt 13140 aatttttttt tactttatct ttaattagct ttagctcttt tttttttttt tgagatggag 13200 tctcactctg tcacccaggc tgagtgcagg ggtgcagtct tggttcactg caacctctgt 13260 ctaccgggtt caagcaattt cttgtgcctc aacctccgga gtagctggga ctacaggcgt 13320 gtgccaccac ttcctggcta attgttttaa attttagtag aaacgggatt tcaccaagtt 13380 ggccagactg gtctcgtact tctgacctca agtgatccgc ccaccttggc ctcccaaact 13440 gctgggatta caggcgtgag ccaccatgcg cccagccata gactatatat ttttgatctg 13500 ataactggtt cagctactaa gtgactaaca ggcaagtagc atctatagtg tggatatgct 13560 ggacaaaagg acattcacct cctgggcagg atggcacaga atgttgagag attttatcat 13620 gctactcaga atggtgtgca atttaaaact tatgagttgt ttgtttctgg agttttccat 13680 ttaatagttc agaccatgga ttgaccgcag gtaactgaaa ctgtggagag tgaaactgtg 13740 gataagggag gactattgta ttgttaagtc agactcatta ggcaatcata actcttgatt 13800 tgccatcaga aatgctgcag aaatatgggt taaaaaaaac tgttcaaaaa tagggtcagg 13860 gatgtccttt aacttgttac ttccaaaatg ttagtgaaaa ctgtggcccc aaagagtgaa 13920 aggaacaaat gactaagaga aaatcttgtt ttcaggatga cagattaaaa aagaagcaac 13980 ttgctgaaac actgaaaatc tctccacttg taagataaca caaaactggc taaaactggt 14040 tggaatgaat atggccaact caagtctgca cagaactaac ttggtgatgt tacagcccaa 14100 atttccacca catattttat actaactccc cccggatttt cacacatgat ctgtgaggta 14160 gcatgaagag gtaactatgc atgcctaagg acttgggaga cctccccatt tccttccacc 14220 aatcacccac taatcccaga atccgccccc aaaccttttc taataactac cttaaagcca 14280 gcatagggag acagatttga gctggactcc tgtcttcttg tgggtcacct tgcaataaaa 14340 agcttttctt ttctcaacac ctggtattat agtattgact tctagttcat cgggcagcaa 14400 gccccttttg gtcggtgact attcttgttc gctgatattt ccattggcca aaatataaac 14460 ctcttagatg aaacttcagt acgtaaatgg cgccacagaa tgctgtgaca tttttctctt 14520 ggattatagc aggttacttt actgaatacc gtaggcagtt ataacacact aagtatttgt 14580 gtatctaaac atagaaaaga tacagtaaaa atatggtaat ttttttcaac ttttagttga 14640 gatttggagg gtatgtgcac atttgttaca agggtatatt gcatgatgct gaggtttggg 14700 gtacaattga accctgtcac ccaggtagtg agcatagtac ccaatcgata atttttcaac 14760 ccttgtccat tccctccccg ttcttgtagt ccccagtttc tgcttttccc atctttatat 14820 ccgtgtgcac cccatgtttt gctcccatgt gtatgtgaga acttgtggtg tttggttttc 14880 tatttctgcg ttgattcgct taggataatg gccttcagct gcatccatgt tgctgcagag 14940 gacgtgattt tattcttctt tatggctgtg tagtattcca tggtgaaaaa tatagtacta 15000 taaccttact aaatcactgt catatatatg gtctatcatt gactgaaatg tatacagtgc 15060 atgatatata tatatatata tctataatgt cttatccatt tcgtgtatta tgagatttga 15120 ttgctaatat tttatacagg agttttgcat ctttttcact agttgacatt gcttgtaatt 15180 ttcctttttt tgtgatgtcc ctgttaggtt ttagaatcaa gtgtataccc gcctcataaa 15240 atgggttgga aaatgttccc accctttctg ttctctggaa aattggtgtt tttttcttaa 15300 agtttggtag acattattgt taaaaccatg gggtcctcga tttttcttca tggaaatgtt 15360 ttcaaattac actttaaatt tctttaaaat ctgagtatag ggctatcaga ctttctgctg 15420 tcttatgtca gtttttaata agttgttttt gtaggcgttt gttatctcac tttcatattt 15480 ttgatataaa gcttttcata atatcattaa tgtctatagt gtctagtagt ttccatcttt 15540 actttctgac attggttatt tgccagtttt aggagtttat caattttatt agtcttttca 15600 aagaaccatc ttttggcttt gttaatcctc ccaatggtgt gttttctttc tcattacttt 15660 ttgctcttta tttccttcaa cttctttttt gcttaatttt aaaataattt cttgagattg 15720 agataagcct caatgatggg tcaccgattt ccagtctttc ttcttttcta attatgcatt 15780 ttaaaccaga aatctttctc taagtgtagc tttagttgca gctcacaagt ttcagatctg 15840 tctctcagtc tggaggttgg agatctgacc atgaccatga aaccatccag tcacaatgtg 15900 gcattatttt tttaattttt tttttttttt ttgagataga gtttcactct tattgcctag 15960 gctggtgtgc aatggtgcga tctcggctca cagcaacctc cacctcccag gttcaagcga 16020 ttcttttgcc tcagcctccc aagtagctgg gattacaggc atgcgccacc atgcccaact 16080 aattttgtat ttttagtaga gatgggggtt ctccatgttg gtcaggttgg tcttgaactc 16140 ccgacctcag gtgatccgcc cacctcagcc tcccaaagtg ctgggattat aggaatgagc 16200 cactgtgccc ggcccaactt ggcattattt acccagaaga gcatgaccat gagaacagta 16260 gaatttgtaa gctttgagtg ggtgactatg agtgtcataa taggtagata ggttatattt 16320 tgggtggtgg taggagaggg cttacagttt gctatgacag ctttttatat ggatcatcct 16380 tagtaaaaga ttatttaatt tttgaaatca aaggggaaaa cactagttta ggctttcttc 16440 tttctttctt ttttagagac agggtcttgc tctgtcacca ggttagaatg cagtggtgca 16500 atattgctca ctgtaacctc aaattcctgg gctcaagtga tcctcctacc tcagcctcca 16560 agtagctagt atttacaggc atgcaccaac acatctggct aattttaaaa attttttatg 16620 gagatgaggt ctcactatgt tgtccagtct ggtcttgaat cctgacctca agtgatcctc 16680 ccccatcagc ctcccaaagt gctgcaatat tttaaatcct gtggtaggtc aagtggttgt 16740 cttctatctt ggggtttata aagtacatgt caagaaattt agggtatggt tagattagct 16800 ttaaaaatgt catgttttat aaaaatcaat gcatcatttt tctgattgaa aatttaacac 16860 aagactcaga atctttttgc agtagtggaa ttacttttat tatagatctt tgcgataatg 16920 aatgatgata catctggcca aaaataggta ctatagtctt ttaggaaaac agctaatctg 16980 cttgaaatat gtgtagaaat aatttagtgc atcagcccat attggcaata acttctctct 17040 aatttttttt tatagaaaat ttttactact ggagatgtca acaaagatgg gaagctggat 17100 tttgaagaat ttatgaagta ccttaaagac catgagaaga aaatgaaatt ggcatttaag 17160 agtttagaca aaaataatga tggtgtgtct ttcttttgta tttatcacca gctatgaaga 17220 agcatttatc atgctttcaa gagtctaaaa ggatgcttat ttaatctctc tggttttaga 17280 tgataattat tatttgtgtt aatacttttt tttagtaatg tgatttttat gtagagttta 17340 tattatttag tgaagaaaac ttatagatag cttttctttt tcattacttt gaaatgtaat 17400 gaattacatt tctgaattaa aaactgtggg cagggcctgt tgtaaatgtt aactatggaa 17460 cattatgctg atttgagtta aacctgtagg ttaaaaataa taattatatt ttcttgtcct 17520 ctgggtaaaa tgagatttct ttttatttgt atagaagaat gacagttgtg tcatctaaaa 17580 tttaaaaaac tttcagatta tcttgcatct gttagttttt ttggaagaat taatttagag 17640 aagatatctc tgatcctgga aattagggaa aaatagcata taaacgttta agtgtgtacc 17700 ttctggttaa gattatgact tctatatttc gattaatagg ttggagtttg tcttaatctg 17760 ttttctgttg ctgtaatgga gtaccacaga ctgggtaatt tatgaagaaa tgaaatttat 17820 ttcttatagt tctggaggct gggaagttca aagttgagcc gaatctggtg agggcctctt 17880 actatgtcat aacatgctag caggcatcac agagcaaatg cactacctca gatctctctt 17940 cctcttctta aaaagccact agtcccatca tgggggccct actctgaaga ccttatctaa 18000 ttctaattgg aaatagggtc ttgaagccct catcactaga ggtaaccttt aacaggaaga 18060 gagaatttat aaaaattata atgcagcacc aaatccctcc ctacttgtga atagtcaagg 18120 tcatttcatt tacagacttg ttattaaaga aacaggttaa acaaatagat tgagaggaaa 18180 tgtggttcat gtctgagatc agcaaacttt tttgtccaga agtccagata ataaatattt 18240 tagctttgtg ggtcatgtgg tctcagttgt agctacttgt ctctgctgct gtacctcaaa 18300 agcagccatg gataatatgt aaatgaatgg ggatgactga tttccaataa aaactttatt 18360 tacaaagata gttaatacac cttatttggc ttgagggtta tagtttgcca tcccctgatt 18420 tacaatgaat attaaagttt aattcaaagc aagttccttc aaacaaacaa actaaactct 18480 agatgatttt gaagattatt cacatctgtg actctcagcc aggaagagct gagtttgggt 18540 tggaaagtag tactattgga acatttgttg cccataagcc ttacaatata tgcccctaag 18600 tctagcctta gtccagtctt ctagcaaaac tcagttttct ttcttctctg caaactttca 18660 ttccaacatc gaccctctgc agttcagatt gtcttgcagg tcagattgtc tgtgtgctgc 18720 tatggtaggc agtagctgag agatggagct accttaagat caattgccag ataatcagag 18780 gtcaattatc ccagtgcata agtagtgtac atatcaattg ttcattttat aaaattctaa 18840 atgaaccaga ggcaataatt aaagatgaaa ttttgatggt atatttgtag gaaatctaca 18900 caatgtttcc ctaatttccc atgtttgtgt attttaaaac aatgtggcat tattggttca 18960 tatttttatt ttttagactt ccttaatgca aaacatatac agttgatcct cattatttgg 19020 ggattctgta tttgcaaatt tgcctactca ataaaattta tccccaaagt aaccccaaaa 19080 tatatactca cagtactttc ccaggcattc atggacatgc acagagcagt gaaaaacttg 19140 agttgctcag catgtacatt cctagctagt agaataaggc aatactctgc cttcttgttt 19200 cagctctcat actattaact agcaagtatc cctttcaagg tctattttgt gccagttttt 19260 gcatttttgt atttttgttg gtaatttcct ttttaaaatg ttccccaaag gtagtgctga 19320 agtgctgtct agtgttccta agtgcaagaa agccatagca tgccttatgg agaaaatata 19380 tgcgttggat aagctttgcc ccaaattcaa tgttagtgaa tcaacagcac acattaaatg 19440 aggtgccttc aaacagaaac agacataaga catggttatg tattaatcag ttgatgaaag 19500 tgttgtaatc agaggctcac aggaacctaa ccctgttttt cctgtaggaa caatggtttg 19560 gtatttgcta attcagtgtt tgcaatgaat atagaacttt atggaagatg attgctgtga 19620 ataatgagaa ttaaccatat ctctttaaga gtgcatttct aaaggagaat attcagaagg 19680 gtatttgcat aatttcttta ctaacagatg ctgcctctca ctgtccttac atggtccaga 19740 ttctcatgct gctccttccc tctccccagg aggattctct cagaatcctg tcatctcctc 19800 cagggtcctt tctccaagaa agtctatcct ttcaccacta acagtaattt tggtcttcct 19860 ctttttctgg agaagtcagc tgtttatgct gcttcagcac cagaccctct cttactttgt 19920 tttgtttcat tctttttcat gtacagtagt cttaggattc tcatgagcct gtgagctgct 19980 agaaggaaat acagcagtgc ttacatttat tgcttctatt ttattttcta ttttctcttc 20040 ctgtcttctg attgttctcc ttctgtccac aaacatgctc taatttccct agtattaaaa 20100 attttctgtc ttttgttgtt cttttatcct tgctccctta tttttactgc cagattttta 20160 tttttattta tttatttttg agatggagtc tcactctgtc acccaggctg gggtgcagtg 20220 gcgcgatctc agctcactgc aacctccgcc tcccagcttc aagcaatttt cctcttttag 20280 cctcccaagt agctgggatt atgggcacct gccaccatgc ctggctgatt tttctatttt 20340 tagtagagac ggggtttcac catgttggcc acactgctct ctaactgctg acctcaggtg 20400 aaccacccgc ctcagcctcc aaaagtgctg ggattgcagg tgtgagtcac tgtgcctggc 20460 cttttactgc cagattttta aaagaatagt ctgtgcttta gctctatttc ctcatttact 20520 acttctcttt aactcagtca tatatgatgt tttgcatagt aaatgtctag taatttatta 20580 aaaatgtaga aataggtact tttaaaatga atagatccta ctttaattga atttatcttg 20640 gagttagaat atcttgattt ggattttagt tctgctactt cttaattaca ttacttggta 20700 aggccacttg tgaagtcagt ctctttggag gaatattatt tatctataag gctgttacaa 20760 ttactgaatt ttaaaaaatg tgtatttatt ttttaatgta tttgttacat ttttagtatt 20820 gatgttggga taggcattta agcaagtcta taactcacct acatgcataa ttttgcctta 20880 atcagtttaa agctttctct taaatgagag atttgaaatt cataatttct gtggttctta 20940 tcagttctga gttttatttt ttgccctttt tattttttta aaggaaaaat tgaggcttca 21000 gaaattgtcc agtctctcca gacactgggt ctgactattt ctgaacaaca agcagagttg 21060 attcttcaaa ggtaagctct tcatgttggt caacaattga ctttcacttt aatatcctgc 21120 attagaactc tgtgtttgta agtgtggctt taaaacacct ccctagtctt cattatgtat 21180 atccaagatc tttttgtctt ttttcctccc attcattttg tatgtgtaca tttatctaaa 21240 gtgtaagaat gggaagtgta agctcagact ggactctttc tttcaaggcc tcaaaggata 21300 gtggaatggc aggaagtaag gttttaactc catagatgag gagctgaaga gttttggtgt 21360 tgctttttct ccatttgatt tctaatgtga cagtaaaact cattgattca aactaagaag 21420 actagcagat tcatcacatt atttaaccta gatgtgactg gaaaaaaggg aaattactaa 21480 gctctccaag ctaacaaaga aatacctgtt taaactttca gaaaacagaa atgcaaattt 21540 gaaccttatt gtctggggca atcagtttga ctatttaagt cagactttta tactcttaat 21600 gttttgtttc atgggataga gcagtaatct ctgcagccca ggtgctctca aatactctgt 21660 tgctataaac acagggcagg aactgatttt ttatgataac gtaaaacaga aaaggacaat 21720 tatattgtat taatattgtt gtgaatattt tcagtcctca cattgtctaa aaatctttct 21780 aaatggcttt gttattgaat ttatctcatt ttatatctgt gccaacagca ttttcatcct 21840 ttctcttcat aatttctttt acaaacagct gctcaagagg aaggctcaaa gtctcaaggc 21900 tgagcacgta atgacttttg ttagtactag atgagaaggg ctttcctgag gaaatgaaaa 21960 cctaaaacat gaaaagaaga taaacagaat ttggacagtg agatatagag catataatat 22020 tctgcttcta aagtaatatt cttctaggaa agtgagggcg tttccctggc tgttaggcca 22080 gaaatcatat tcctatattt tctttgatag ctttaggaat aatgcaaatt ctaagcccaa 22140 gcttcagaat agactaagaa gtattagctt agctgccatg acaaaatacc ataggctgga 22200 tgcattaaac aatggaaatt tagtttttca caggtctggg agctgggaag tttaagatga 22260 gagtgccagc atggttgggt tgtagtgagg gctctctttc tggcttgcag atagacccct 22320 tctcactgta ttgtcatatg gcagagagag agagagagag agagagagag agagagaggg 22380 gatctttctc ttgctttcta ttataaggcc atagtcctgt tggatcaggg ttccattctt 22440 atgactttat ttgactttac ccccctaaga tgctatctcc agatataatc acacggtggg 22500 ttagggcctc aacatttgga tttgggaggg acacagctca gtccatagca aaggataatg 22560 cagagggttg gatatttaaa agtagctaca caatttttaa tataaatatt ttatggtaac 22620 tttttttttt ttttgagatg gagtctagct ctgttgccca ggctggagcg caatggtgcg 22680 atctcagctc actgcaacct ccgcctccca ggttcaagca attctcctgc ctcagcctcc 22740 tgagtagttg ggactatagg cacgcgccac cacgcctggc tatttttttt ttatttttac 22800 tagagacggg tttgcaccat attggtcagg cttgtctcga actcctgaca tcaggtgatc 22860 cacccatctt ggcctcccaa agtgctggga ttacagaagt gagccaccgc gcctagccag 22920 cagctttact gagatgtaat tcacatgcca taaattcact tttctaaagt atacaattca 22980 gtgacttaaa acatttattt atttttaaat tgacagaatt acatgtattt atcatgtaca 23040 acatgatgtt ttgaagtata tgtacattgt ggagtgacta agtctagcta attaacatga 23100 tacatctcat acttaatgat ttctgtggtg agaacacttt acatccattc tcttagtatt 23160 tttcaagaat ataatatatt attattaatt gtagtcttca tgttgtatag tggagctctt 23220 gaacttattc ctcatgtcaa gctgaaattg tgtgtccttt aacacaaacc atacccgact 23280 cccaaagtat tctgctctct gcttctatga gattaacttt ttctgattcc acatgagtga 23340 gatcatgcag tatttatttg tctttacctg gcttatttca ttcatattgt tacagataac 23400 aggatttcct tcttttttta atggccgaat agttttctat tgtatatgta tagcacattt 23460 tctctcttca tgcattggtg gacacttagg ttgattccgt atcttggcta tcgtgaatag 23520 tgctataatg aacatgggaa tgcacatggc tctttgacat attgatttca ttttatatat 23580 gtgtatatat atatgtatac acacacatac atacagtggt gggattgcag gatcatatgg 23640 tagttctata tttaattttt aaaggaactc catactgctt tccataatgg ctgtattagt 23700 ttaactcctc accaacaggg tgcaaaagtt cccttttctc tacatacttg ccaacacttg 23760 ttatcttttg tctctttggt aatagtcatt ctaagtgtag tatgaggtga tatctcattg 23820 tggcttttat ttgcatttct gtggtaatta gtgatatcga gctttttttt ttttttgtac 23880 tttggccatt tgtatgtctt tgaaaaatgt ctattggggt tttttggttg tttatttgag 23940 gttttnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 24000 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 24060 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 24120 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 24180 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 24240 nnnnnnnnnn nnnnnnnccg gggttcccgt cattctccct gcctcagcct ccccgaagta 24300 gctgggacta ccagggcacc cgcccaccac ggcccgggct aattttttgt atgttgagta 24360 gagacggggt ttcactgtgt tagccaggat ggtcttgatc tcctggcctc gtgatctgcc 24420 cgcctcggcc tcccagagtg ctaggattac aggcgtgagc caccgcgcct ggcctgattt 24480 ctagtttttt attattgtgg tcggaaaaga aacttgatat gatttcattc tgcttaaatt 24540 tgttaagact tgttttgtgg cctaacatat gatatcccct ggtgcatgtt ccatgtgcag 24600 ttgagaagaa tgtgtattct cttgccatta ggtgaaatgt tttatgtctg atctgtccat 24660 ttgttctaga gtatagttta agtctgatgt ttcttactga ttttctgttg agatgatttg 24720 tctattgctg aaggtagggt gttgaagtcc cctactattg ctgtattgca gtctctctct 24780 cctttcagac gtattaatgg tttttatttt attttatttg ttgttgttgt tgttgttgtt 24840 gttgtttttg agacggagtc tcactctgtc accaggctgg agtgcagtgg cagggtctcg 24900 gctcactgca gcccccgtct cacggttcaa gcgattctcc tgcctcagcc tcccgagtcg 24960 ctgggactac aggcgcatgc caccacgccc agctaatttt tgtattttta gtaaagacgg 25020 ggtttcacca tgttggccag gatggtcttg atctcttgac ttcatgatcc acccgccttg 25080 gcctcccaaa gtgctgggat tacaggtgtg agccaccacc cctggccaat gtttggtatt 25140 tatctttagg tgctctgatg ttgggttcat atatatttat aaaaaacaat agctacataa 25200 cttattaagg gatatgcaat ataaaatata taaattgtga cactgaaaat ttaaaatggg 25260 aggagtggag taaaagtacc ttcatataac ttactattat atcctcttat tgaattgacc 25320 cttttatcat tatataggaa ctttgtttct cctttacaac ttctgactta aagtttgttt 25380 tatatgatat aagtaaagtt actcctgctc tcctttggtt tctgtttcca tggaatatct 25440 ttttccattc cttcaccatc agtctgtgtg tatttttaca gatgaaatga gtctgtcatg 25500 ggcagcatat agttggatct agttttttta atccactcag acactgtgtt ttttgattgg 25560 ataatttaat ccattcatgt tcaaggtaat tattgataag taaggacttt gtactaccat 25620 tttgcttatt gtttcatggt tcttttatag atcctttatt cttttcttcc tctcttgctg 25680 tctttttttt gtggttaagt gattttctct agtggtatgt tttgatttct tgctttttat 25740 tttttgtgta tctcctattg gtttttggtt tgtggttacc aagaggttac aaaaaacatc 25800 ttaagagtta taatagttta ttttaacttg ataacttaat ttttattgca aaaacccccc 25860 aaaacaaaaa aatctacact tttacttaat cccctgaaat tttgaatttt tgatgtcaca 25920 gtttacctct tttcatattg tgtatccctt aaattattgt agctattatt acttttaata 25980 gttttctctt tcctactaca gatgtaagtg atttgcatac catcattaca gtattatttt 26040 gaatttacct gtgtactttt ttttatcagc cagttttata ctttcagatg tttttgtgtt 26100 actcattagc atctttttct ttcagcttga ggagctcctt ttacgtttct tataaaatag 26160 gtgcggtcat gattatctcc ctcagctatt gtttgtctgg gaaagtatct ctccttcatt 26220 tctgaaggac actttgctgg gtacattacc cttggttggt atttttctcc ttgaacgctt 26280 taaatatatc atccctttct ctcctgacct gttaggtctc tgctgaccag tctgtttcca 26340 accatattgg gactgtctta tatgttattt gcttcttatc ttttgctgtt ttcaggatcc 26400 tctcattgtc tttgattttt gatagtttga ttgtaatatg tcttggggta gtcttgtttg 26460 gattgaatct gattagagac cttggacttt tcctgcatgt agatatttac ctctttctcc 26520 aggtttggaa aattttctgt tactgtttct ttaattaagc tttttacccc ttttatcttc 26580 cttttctcct tcttcaactc ctgtgactca aaactttgct cttttgatgc tgttccataa 26640 atcttgtaag ctttcttcat tcattttcat tcttttttct cctctgtgta ttttcaaata 26700 acctgtcttt gagttcatag tttctttctt cttcttgatc acttctgcag ttgatgctcc 26760 catattgcat tttaattttg ttcattgtat ttttcagccc catgatttct gtttgatttt 26820 ttcttttatt atttcatctc tttattacct ttctctttgt ggtcactcgt tattttccta 26880 atttcattga attgtttctt tgtattttct tgaagtttgc tgagctttct ttgaattcta 26940 tgtcagttca tacatctctg tttctttagg gatggtcgct ggtactttat tttgtttctt 27000 tagtggtgtc atttgttcct gattgttgtt gatgtttgtg gccttgtgtt tacatctgtg 27060 catttgaaga agtaggcact tatttcagtc tttgcagact ggctttgtct gagaatgccc 27120 ttcaacagtc agcctgtcta gagattcttt aatatttaat taaatatctt taatattttg 27180 aagaacttcc aaattgtttc taaagtggct gcaccatttt ataatcccag cagcaatgaa 27240 tgaaggtttc agtttctcca tagctatatg aatactcatt actgtctgtc ttttcatttt 27300 ttgattttta tttttttttt gagaaagggt cttgctctgt catcccatct ggagtgcaat 27360 ggcacaatca tggctcattg cagcctcaac ttccctggct caattgatcc tctcacctcc 27420 tgagtacctg ggactacagg cattgtacca caatgcctgg ctaattttta tattttttgt 27480 agagatgtgg ttttgccatg ttgcctggtg tattagtcca ttctcatgct gctataaaga 27540 actgcctgag actgggtaat ttataaagga aagaggttta attgactcac ttttgcttgg 27600 ctgaggagcc ctcaggaaac ttacaatcat ggtggaaggg gaagcaaaca cgtccttctt 27660 cacatgatgg caggaagagc agtgcctagc aaagagggaa aaaaaccctt ataaaataat 27720 cagatctcat gagaagttac tcactatcat gagaacatca gaatgagggt agcctcctcc 27780 atgattcaat tacctcccac tgggtccctc acgtgacatg tggggattat tggaactata 27840 attcaaaatg agatttgggt gaggacacag ccaaaccata tcatttttgc cctggtccct 27900 cccaaatccc atgttctcac attgcaaaac acaataatgc ctttccagca gtcccccagc 27960 gtcttaactc attccagcgt taacctaaaa gtccaaggtt tcatcagaga caaggcaagt 28020 cccttctgcc tataagcctg taaaatcaaa agcaaggtag ttattatact tcctagatac 28080 aatgagggta caggcattga ttaaatatac ttgttccaaa tgggagaaat tggccaaaat 28140 gaaggggcta caggccccaa gtaagtccga aatctagtgg aatagtcaaa tcttaaagct 28200 ccaaaatgat ctcctttgac tccacatcac acatccagct catgctaatg caagaagtgg 28260 gctcccatgg ccttgggcat ctgcactcct gtggcttttc agggtacaga cccccttctg 28320 gctcttttca caggctggcg ttgagtgtct gtggcttttc caggtgcatg gtgcaagctg 28380 tcggtggatc tactattctg ggtactggag gatggtggcc ctcttttcac agctccacta 28440 ggcagtgctc cagtggggac tctgtgtgaa ggctccaacc ccacatttcc cttctgcact 28500 gccctagcgg aggttctcct caagggctcc acccctgcag caaacttctg tctggacatc 28560 caggcatttc catacatcct ctgaaatcta ggcagaggat ctcaaacctt aattcttatc 28620 ttctgtgtac ccgcagactc aacaccttgt ggaagctgcc agggcttggg gcttgcacct 28680 tctgaagcca tggcctgagc tgtaccttgg ctccttttag ccatggctgg gatgcagggc 28740 accaagtcct gagactgcac aaagcagcaa ggccctgggc ctggcccagg aaaccatttt 28800 ttcctcctgg gcctctgggc ctatgatggg agggcccttc ctgaagacct ctgaagtgcc 28860 ctggaggcat tttccccatt gtcttagtga ttaacatttc actccttgtt tcttatgcag 28920 atttctgcag ctggcttgaa ttttttcctc agaaaataga tttttctttt ctgtcacatc 28980 atcagggtgc aaatttgaca aacttttgtc ctctgcttcc tgtggaatgc tttgccactt 29040 agaaatttct tctgcctgat accccaaatc atctctctta ggttcaaagt tccacagatc 29100 tctagggcag gggcaaaaag ccaccagtct ctttgctata gcataacaag agtcatcttt 29160 gctccagttc ccaacaagtt cctcatctcc atctgagatc atctcagcct ggacttcatt 29220 gcccatatta ctgtcagcat tttggtcaaa gcaattcaac aagtctctgg gaacttacaa 29280 actttcccac ctctttttgt cttctgagct ctccaaattt ttaagaagtt ccaaactttc 29340 ccagtcttct tctgaacctt cctaactgtt ccaacctctg cctgttaccc agttccaaag 29400 tcagttccat atttttgggt atccttatag tagcacccaa ctcctagtac caatttactg 29460 tattagttca ttctcacgct gctataaaga accacctgag aatgggtatt ttataaagga 29520 aagaggttta attgactcac agtttcgcgt ggctggggag gcctcagata acttacagcc 29580 atagcagaaa gggaagcaaa catgtccttc acatggtggc aggaagaaga agtgctgagc 29640 aaagagggaa aagccctata aaaccatcat atctcgtgag aactcactca ctatcatgag 29700 aacagcagca tggggttgac caccccccat aattcaatta cctcccacca gctgtctccc 29760 gtgacacatg gaaattatgg gaactacaac tcaagatgag atttgggtgg ggacacagcc 29820 aaaccatatc atctaggctg gtatcgaaat cctgggctca agcaatccac ccaccttgcc 29880 ctaccaaagt gctgggatta caggcatgag ccaccatatc tgaactgtct tttgatttct 29940 tttgatttta accatccatt gtttctgctt ctctagataa ccctgactaa tatataattg 30000 gtatgaagtg atatctcatg gctttgattt atatttcttt catggctagt gacttttttt 30060 gtacttttgg gatattgtta ttattattat tattattact agtgtttata cttcttcagt 30120 aaaagtgtta gaaacaattt ttaaaggcag aatgtgacca gagtttcctg tagttatata 30180 accatcatgg accttccctc aagtgctaag ccattagtgt tactcatgtc actccaaatg 30240 tcagcttgtt ttcttccatt tcactgtctc tttgtgtccc aaacttgaat tcatgggaaa 30300 aacatctgaa tggtgcttaa tatggtttgg atatttgtcc cctccaaatc tcatgttgaa 30360 atatgacctc cagtgttgga agtagggact acttgggtca cgagagtgga tccttcatta 30420 atggcttggt aataagtgaa ctctattagt tcatgaaagc tggttgttga taagagcctg 30480 gcatctcatt tctcttgtcc ttctctcacc atctgacaca cttgctcacc ttttttcttc 30540 agccatgagt aaaagcttcc tgaggtctca ccagaaactg agcagatgtt ggtgccatgc 30600 ttgtacagtc tgtagaactg tgagccaaat aagcctcttt tctttataaa ttaccgagtc 30660 tcaggtgttc gtttaaaaca acacaaaaca gactaacaca gtgttgattg aaacagctgt 30720 gactgggtca tcagggtgta agagaggagt cactgagttg aaatatagcc tcctacttac 30780 acctgttcag tagaagctgt agatatgaag tagctgaagc aggcattccc tctgaaacat 30840 gtgtttcaca tatgtcataa ttatcttctg ctctcatttt tcttttaggc ttttgtctcc 30900 atctcatttc ccctgtttac tctcattttc atatctttac atttctttct ccagaattgt 30960 tcagaagctt ggaacccttc actccagtta ttctttgact atgcaatttg tttctgtgct 31020 tcatggcact tatggtttgt aatccttgac ttgtttgtat agctcagtgg ttaggagtac 31080 agtttggagt tagaatgcct gggttgaaac tcttaattct actctactta ctagtcttgt 31140 gactataaca aaattcttag cctctctttg tctgtaaaat ggagagtata gtaaatacat 31200 gggcttgttt taaggattaa atgagttaac atgtgaaata cttagaacaa tgcctggcaa 31260 atgctcaatg aatattgagt attgcttgct tttgtttagt gccatgcctg ttgttcccac 31320 tgagggcaca gaccatgtgt atctggttaa cagttctatg tccaccacgt tgcaataatg 31380 gactctcaga aaatattgaa gaatatgtta aagaatgagt agaattatgc tactgaaaag 31440 ggtgagtgga aggtaggtag gggaaaggac atatacagcc ctggaggcag catatatggg 31500 gaatgggtca cacagtgttt cttggtactc tctagaccat agtgggccac ctcttagcta 31560 gtggcctatg gattatttca gcagtctgtt ggaaacatcc atgaatatga taataatgac 31620 ccatttgtgg gttctaagaa aaaggacaac tacaatacta gacaataata gtatgtaagt 31680 taggagggaa ggggatgatt tgtattaaac tgttctaaaa ttcttacctt atttaggatg 31740 atggggtcag acattaactt tagactttgt tatatatatg tggtaaaatt tcaaggtaaa 31800 ccattgaaac tgtagtagtt gagtatataa cttccaaatc aggggggaaa gaaatggaat 31860 aagaaaataa atacataaac ataagattga aacaatccaa tgaagagtag agagaagagg 31920 gaaaaacata gaaagaatga gataattaga aagcaatagg taagatgtga gaaataaatt 31980 caagtacagt aaaactccac taaaatgtgc cctgcagtaa tgttggggca tgatttccct 32040 tcatccccat tctcaaatgg ggcagcctaa atagcgttct tatcctgttt ccctgggggt 32100 ttgaggtggg tgacgagtaa gttagaagat aatcaccttc tgatcagtta ggactttctc 32160 agtttagtct tcaattaata aaaattaatg taaatttcat cagaaggcag agattgtcag 32220 atgaaagaac aagcaaaata aaagtcttac tgaaaaaaag ctggggtagc tatgttaata 32280 tcaactgtta attattatta ataatctatt aataatagat tatatagtaa aaacattaat 32340 aaaaatagag tgtcactaca ttttaaaatt cagtatgagg atatacaatt tttaagctgg 32400 ttgataaaat tctggggatt aattggcaaa tccatcatag tggtgagaga ttttaacaca 32460 attcttcctg tatttgatag gtcaagcaga gaaaaacttt agtgaagaca aaaacttcta 32520 aatacataag cttgatttaa tgggcatgta ataggaccta gcatcaaaaa attagaaaaa 32580 atattttttc ttaggtattt atggaacatg tataaaaatt gatttcgtag taggccataa 32640 agccaggttc aacacatttc aaagaactgg tatcacaaga actgctttct ctgaccacta 32700 tgcattaaaa tagaagttaa ttacagacat aaattataaa aatgccaata ttttaaagtg 32760 tgatatacac ttctcaactt atgggtcaaa ggaaatcgta agtggaaatt caaggacacg 32820 ttgacttgaa aacattaaaa cttatggaat atttctaaga tggaacttgt atgaatttta 32880 tagtctgaaa gcttttatta gaaaagaatt aagtctgaaa attaatgtgc taagttaggg 32940 gagagaaaat ggaataatct cgaagaaggt aggaggaagg agataataaa gaatatatag 33000 caaagatgca gtaacaggat caacaaagcc agaaactgtt ggaaaagaca agcctctgga 33060 aagattgatg aagaaaaaag agaaatgaga tgtaaataaa tcatgttcag ttataaatag 33120 gcacataagg acttttaaaa aactaataaa ataatatgaa tcattaatgc caataaattt 33180 gaaaacagac aaagtaggtg aatttctaga aaaatataac ttactgggac tgaatgaaga 33240 agcaacagct tatagtacct aagcaattga agagattggg tcagtaattt aaaattttct 33300 cataaacaaa acgttagccc cagatggttc ttgcaaatga ttaaagaaca gatgtacaaa 33360 catttccaga gtgtagaagt acactgtcct atcctttcta ggagatcatt ataacaccaa 33420 aagcagacag tatatgaaac agggaaatta gaggccaaga tacctatgac ttatatgtaa 33480 aaatttaaag aaaatattag caaactgaat cagccatttt aaaaaatata ccacaatcaa 33540 tgcattcata agagcagctt aacaaaattt gttagaaggc attaaagaag actcagtata 33600 gaaaagatgt accttctctc caaattggtg atagagattc aatgccatta aaaaaaccca 33660 cctggttttt ttgaggaact tgtcaagctg agtctcaaat ttatatcaaa gagcaaaggc 33720 ctaagaatat ccaggacatt cctgaagaac tgtaaggagc caggggcctg ccctatcaga 33780 taccaagggt tgttattaag ccataaccaa gtcagtgctg tttctacaga aacagacaag 33840 ttaacaagtg aaacataata gagagcccag aaacagaccc atccatattt tggatttgtc 33900 acgtgaaaga agtagctttg caaaactttg ggaaaaggag agtgtgtgca atagatgatg 33960 ctcgtgctca tgcagacaaa aaggaaattg ggatacctgc ctcttaccgt acacaaacac 34020 caacctaaac gtgaaagtta aactataaca gcttgaggtg gtggggaaga aatatcttta 34080 tctcagtgta gggaagaatt tattttaaaa agaagacaca aaaggccata cataggaatg 34140 aaaagattga attcagctgc attaaaaaga ttaaattcag ctgcgttaaa atcaagagca 34200 tctgtacttg gacagcatag agtggaaaga caaagagaag gtatttgcca gcttataact 34260 tgaaggatta gaatgaatga tataaagaac tatgtaaata agaaaaagac atacaaccgg 34320 ttagaaaaac gggcaaagac atgaacagca tatttcacgt gaaggaaaca gcggtagcaa 34380 atgaacatgg taagagatgc tcaacacgtt tagtaatttg aagggaaatg caagttatac 34440 ccacagcaag actatcttat ctaggaagtt tgtcaatacc ctaaatgttc tgtggtttta 34500 agctacagag tttgtaattc atttatttat tcaataaata ctcagtggca ggcactgttt 34560 tagaaacctt ggttataact ttgaatgaaa ttaaaaaaaa tccttgcctt gtggaggatg 34620 cttatgtgtg gggagttggg tggtggggtc aaacaacaat tacattaaaa tagaaaatag 34680 tgacataaat aaacctataa atattgcaac ccagagttat attataaatg taagtagtga 34740 ctaggactct catgcagata tacctctgtg ctgggacaaa tgaaagttta agtgtaattt 34800 cccatatgca agtcaaaata aaaagtgaca ctagaaaaca caataatgaa tatctgaaaa 34860 ttgcatttta tttgactgcc atccttttgc atcattttca tactaattat agaataaaat 34920 ttgtaggatg caccaaagct ttttttagag acatccatta attcaataaa taaatgagca 34980 ccttctttgt gccagcagct gtaagaggtg gcccaaggaa gggaataaaa cagtcaaaat 35040 cctggtacac tcagagtttc tcttaggaga aaacagatac aaatggcatt aattaccaag 35100 aaacttgtaa aacaagccaa atattaatga taaatatttg agtacagtat gttaatttta 35160 agattgaaaa tgaggtgcca ggatttctta agactcaaag gcgaagatgg ctgaatagga 35220 acagctctgg tctacagctc ccagcgtgag cgacgcagaa gacgcatgat tgctgcattt 35280 ccatctgagg taccgggttc atctcactag ggagtgccag acagtgggcg caggtcagtg 35340 ggtgtgtgca ccgtgcgcga gctgaagcag ggcgaggcat tgcctcactc gggaagtgca 35400 aggggtcagg gagttccctt tcctagtcaa agaaaggggt gacagatggc acctggaaaa 35460 tcgggtcact cccacctgaa tactgcactt ttctgacggg cttaaaaaat ggcgcaccag 35520 gagattatat cctgcacctg gctcggaggg tcctacaccc acggagtctc gctgattgct 35580 agcacagcag tctgagatca aactgcaagg cggcggcgag gctgggggag gggcacccgc 35640 cattgcccag gcttgcttag gtaaacaaag cagccgggaa gctcaaactg ggtggagccc 35700 accacagctc aaggaggcct gcctgcctct gtaggctcca cctctggggg cagggcacag 35760 acaaacaaaa agacagcagt aacctctgca gacttaaatg tccctgtctg acagctttga 35820 agagagcagt ggttctccca gcacgcagct ggagatctga gaacgggcag actgcctcct 35880 caagtgggtc cctgacccct gacgcccgag cagcctaact gggaggcacc ccccagcagg 35940 ggcacactga cacctcacac agccggttac tccaacagac ctgcagctga gggtcctgtc 36000 tgttagaagg aaaactaaca aacagaaagg acatccacac caaaaaccca tctgtacatc 36060 accatcatca aagaccaaaa gtagataaaa ccacaaagat ggggaaaaaa cagagcagaa 36120 aaactggaaa ctctaaaaag cagagtgcct ctcctcctcc aaaggaacgc tgttcctcac 36180 cagcaacgga acaaagctgg atggagaatg actctgacga gctgagagaa ggcttcagac 36240 gatcaaatta ctctgagcta tgggaggaca ttcaaaccaa aggcaaagaa gttgaaaact 36300 ttgaaaaaaa tgtagaagaa tgtataacta gaataaccaa tacagagaag tgcttaaagg 36360 agctgatgga gctgaaaacc aaggctcgag aactacatga agaatgcaga agcctcagga 36420 gctgatgcga tcaactggaa gaaagggtat cagcgatgga agatgaaatg aatgaaatga 36480 agcgagaagg gaagtttaga gaaaaaagaa taaaaagaaa cgagcaaagc ctccaagaaa 36540 tatgggacta tgtgaaaaga ccaaatctat gtctgattgg tgtacctgaa agtgacgggg 36600 agaatggaac caagttggaa aacactctgc aggatattat ccaggagaac ttccccaatc 36660 tagcaaggca ggccaacatt cagattcagg aaatacagag aacgccacaa agatactcct 36720 tgagaagagc aactccaaga cacataattg tcagattcac caaagttgaa atgaaggaaa 36780 aaatgttaag ggcagccaga gagaaaggtc gggttaccct caaatggaag cccatcagac 36840 taacagcgga tctcttggca gaaactctac aaaccagaag agagtggggg ccaatattca 36900 acattcttaa agaaaagaat tttcaaccca gaatttcata tccagccaaa ctaagcttca 36960 taagtgaagg agaaataaaa tcctttacag acaagcaaat gctgagagat tttgtcacca 37020 ccaggcctgc cctaaaagag ttcctgaagg aagtgcttaa cttggaaagg aacaatcagt 37080 accagccgct gcaaaatcat gccaaaatgt aaagaccgtc gagactagga agaaactgca 37140 ttaacaaacg agcaaaataa ccagctaaca tcataatgac aggatcaaat tcacacataa 37200 caatattaac tttaaatgta aatggactaa atgctccaat tgaaagacac agactggcaa 37260 attggataca gagtcaagac ccatcagtgt gctgtattaa ggaaacccat ctcacatgta 37320 gagacacaca taggctcaaa ataaaaggat ggaggaagat ctaccaagca aatggaaaac 37380 aaaaaaagac aggggttgca atcctagtct ctgataaaac agactttaaa ccaacaaaga 37440 tcagaagaga caaagaaggc cattacataa tggtaaaggg atcaattcaa caagaagagc 37500 taactatcct aaatatatat gcacccaata caggagcacc cagattcata aagcaagtcc 37560 tgagtgacct acaaagagac ttaaactccc acacattaat aatgggagac tttcacaccc 37620 cactgtcaac attagacaga ccaatgagac agaaagtcaa caaggatacc caggaattga 37680 actcagctct gcaccaagca gacctaatac acatctacag aactctgcac cccaaatcaa 37740 cagaatatac atttttttca gcaccacacc acggctattc caaaattgac cacatacttg 37800 gaagtaaagc actcctcacc aaatgtaaaa gaacagaaat tatagcaaac tatctctcag 37860 accacagtgc aatcaaacta gaactcagga ttaagaatct cactcaaaac cgctcaacta 37920 catggaaact gaacaacctg ctcctgaatg actactgggt acataacgaa atgaaggcag 37980 aaataaagac gctctttgaa accaacaaga acaaagacac aacataccag aatctctggg 38040 acgcattcaa agcagtgtgt agagggaaat ttatagcact aaatgcccac aagagaaagc 38100 aggaaagatc caaaattgac accctaacat cacaattaaa agaactagaa aagcaagagc 38160 aaacacattc aaaagctagc agaaggcaag aaataactaa aatcagagca gaactgaagg 38220 aaatagagac acaaaaaacc cttcaaaaaa ttaatgaatc caggagctgg ttgtttttga 38280 aaggatcaac aaaattgata gaccgctagc aagactaata aagaaaaaaa gagagaagaa 38340 tcaaatagac acaataaaaa atgataaagg ggatatcacc accaatccca cagaaataca 38400 aactaccatc agagaatact acaaacacct ctatgcaaat aaactagaaa atctagaaga 38460 aatggataaa ttcctcgaca catacaccct cccaagacta aaccaggaag aagttgaatt 38520 tctgaataga ccaataacag gatctgaaat tgtggcaata atcaatagct taccaaccaa 38580 aaagagtcca ggaccagatg gattcacagc cgaattctac cagaggtaca aggaggaact 38640 ggtaccattc cttctgaaac tattccaatc aatagaaaaa gagggaatcc tccctaactc 38700 attttatgag gccagcatca tcctgatacc aaagccaggc agagacacaa caaaaaaaga 38760 gaattttaga ccaatatcct tgatgaacat tgatgcaaaa atcctcaata aaatactggc 38820 aaactgaatc cagcagcaca tcaaaaagct tatccaccat gatcaagtgg gcttcatccc 38880 tgggatgcaa ggctggttca atatacgcaa atcagtaaat gtaatccagc atataaacag 38940 aaccaaagac aaaaaccaca tgattatctc aatagatgca gaaaaagcct ttgacaaaat 39000 tcaacaacac ttcatgctaa aaactttcaa taaattaggt attgatggga tgtatctcaa 39060 aataataaca gctatctatg acaaacccac agccaatatc atactgactg ggtaaaaact 39120 ggaagcattc cctttgaaaa ctggcacaag acagggatgc cctctctcac cactcctatt 39180 cgacatagtg ttggaagttc tggccagggc agttaggcag gagaaggaaa taaagggtat 39240 tcaattagga aaagaggaag tcaaattgtc cctgtttgca gacgacatga ttgtatatct 39300 agaaaacccc attgtctcag cccaaaatct ccttaagctg ataagcaact tcagcaaagt 39360 ctcaggatac aaaatcaatg tacaaaaatc acaagcattc ttatacacca gcaacagaca 39420 gagagccaaa tcatgagtga actcccgttc acaattgcta caaagagaat aaaataccta 39480 ggaatccaac ttacaaggga tgtgaaggac ctcttcaagg agaactgcaa accactgctt 39540 aatgaaataa aagaggatac aaacaaatgg aagaacattc catgctcatg ggtaggaaga 39600 atcagtatcg tgaaaatggc catactgccc aaggcaattt acagattcaa tgccatcccc 39660 atcaagctac caatgacttt cttcacagaa ttggaaaaaa ctactttaaa gttcatatgg 39720 aaccaaaaaa gagcccgcat tgccaagtca atcctaagcc aaaagaacaa agctggaggc 39780 atcatgctac ctgacttcaa actatactac aaggctacag taaccaaacc agcatggtac 39840 tggtaccaaa acagagatat agaccaatgg aacagaacag agccctcaga aataacgccg 39900 cacatctaca actatctgat ctttgacaaa cctgagaaaa acaagcaatg gggaaaggat 39960 tccctattta ataaatggtg ctgggaaaac tggctagcca tatgtagaaa gctgaaactg 40020 gatcccttcc ttacacctta tacaaaaatc aattcaagat ggattaaaga cttaaacgtt 40080 agacctaaaa ccataaaacc cctagaagaa aacctaggca ttaccattca ggacataggc 40140 atgggcaagg acttcatgtc taaaacacca aaagcaatgg caacaaaagc caaaattgac 40200 aaatgggatc taattaaact aaagagcttc tgcacagcaa aagaaactac tatcagagtg 40260 aacaggcaac ctccaaaatg ggagaaaatt tttgcaacct actcatctga caaagggcta 40320 atatccagaa tctacaatga actcaaacaa atttacaaga aaaaaaacaa acaaccctat 40380 caaaaagtgg gtgaaggaca tgaacagaca cttctcgaaa gaagacattt atgcagccaa 40440 aaaacacatg aaaaaatgct caccatcact ggccatcaga gaaatgcaaa tcaaaaccac 40500 aatgagatac catctcacac cagttagaat ggcaatcatt aaaaagtcag gaaacaacag 40560 gtgctggaga ggatgtggag aaataggaac acttttacac tgttggtggg actgtaaact 40620 agttcaaccc ttgtggaagt cagtgtggca attcctcagg gatctagaac tagaaatatc 40680 atttgaccca gccatcccat tactgggtat atacccaaag gactataaat catgctgcta 40740 taaagacaca tgcacatgta tgtttattgt ggcactattc acaatagcaa agacttggaa 40800 ccaagccaaa tgtccaacaa tgatagactg gattaagaaa atgtggcaca tttacaccat 40860 ggaatactat gcagccataa aagatgagtt catgtctttt gtagggacat ggatgaaatt 40920 ggaaatcatc attctcagta aactatcaca agaacaaaaa accaaacacc gcatattctc 40980 actcataggt gggaattgaa cagtgagaac acatggacac aggaagggga acatcacact 41040 ctggggactg ttgtggggtg gggggagggg gagggatggc attgggagat atacctaatg 41100 ctagatgacg agttagtggg tgcagcgcac cagcaaggca catgtataca tatgtaacta 41160 acctgcacat tgtgcacatg taccctaaaa cttaaagtat aataataaaa aaaaaagact 41220 caaaggcaca gtcactgaca gtttgatttt ttataatagc tgttaatttt cctaacttcg 41280 aggaagttga tagcatgttt tgagtatatt tcaaaactac attcaaatgt tgcaatagaa 41340 cattaagaat tatcttcatg atccactaag tgcatgaaaa aaatggataa tgaatctatt 41400 cattaccatc gtttaatatt ttatcttcaa gtttttgtgt tttgtagctc attggcagag 41460 tttgacagag tgctgaaagt attctttagt gagctggctg taatttttgg gcccattttt 41520 atctagataa ttaaaactat ctgacaggac cataaaatgc ttgctgccat ttccaacaac 41580 ctatatttgt ggatggggtt ttttaattta atgagaatat tatgttagaa aagaaactgt 41640 cattctgtaa agtggccaat aatgttagtt ttatttatca atttagtttt gtactttgat 41700 cattttttta aaatttcagc attgatgttg atgggacaat gacagtggac tggaatgaat 41760 ggagagacta cttcttattt aatcctgtta cagacattga ggaaattatc cgtttctgga 41820 aacattctac agtaagtcta ctttatgtat ttatacttat ttggagctat aaaccatagg 41880 tacagttatc acccaagaac actctgtaac acttatgggc caggatacct gagtcccagt 41940 agctccttaa cctgtagagt tctatttatt ctattaggca tagatttata gagtattaaa 42000 caaaaaaaaa cagctctccc tctccctctc cctctctctc cccctcccca cggtctccct 42060 ctccctctct ttccacggtc tccctctgat gccgagccaa agctggactg tactgctgcc 42120 atctcggctc actgcaacct ccctgcctga ttctcctgcc tcagcctgcc gagtgcctgc 42180 gattgcaggc gcgcaccgcc acgcctgact gtttttcgta tttttttggt ggagacgggg 42240 tttcgctatg ttggccgggc tggtctccag ctcctgaccg cgagtgatcc accagcctcg 42300 gcctcccgag gtgctgggat tgcagacgga gtctcgttca ctcagtgctc aatggtgccc 42360 aggctggggt gcagtggcat gatctcggct cgctacaacc tccacctccc agccgcctgc 42420 cttggcctcc caaagtgcca agattgcagc ctctgcccag ccgccacccc gtctgggaag 42480 tgaggagcgt ctctgcctgg ccgcccatcg tctgggatat gaggagcccc tctgcctggc 42540 tgcccagtct ggaaagtgag gagtgtctct gcccggccgc catcctgtct aggaagtgag 42600 cgtctctgcc cggccgccca tcgtctggga tgtgaggagc ccctctgcct ggctgcccag 42660 tctggaaagt gaggagcgcc tcttcccggc cgccatccca tctaggaagt gaggagcgtc 42720 tctgcccggc cgcccatcgt ctgagatgtg gggagcgcct ctgccccgcc gccccgtctg 42780 ggatgtgagg agcgcctctg ctcggccgcc ccgtctgaga agtgaggaga ccctccgccc 42840 ggcagccgcc ccgtctggga agtgaggagc gtctccgccc ggcagccacc ctgtccggga 42900 gggaggtgga ggggtcagcc ccccgcccgg ccagccaccc catccgggag gtgaggggtg 42960 cctctgcccg gccgccccta cagggaagtg aggagcccct ctgcccggcc accaccccat 43020 ctgggaggtg tacccaacag ctcattgaga acgggccatg atgacaatgg cggttttgtg 43080 gaatagaaaa aggggagagg tggggaaaag attgagaaat cggatggttg ctgtgtctgt 43140 gtagaaagag gtagacatgg gagacttttc attttgttct gtactaagaa aaattcttct 43200 gccttgggat cctgttgatc tatgacctta cccccaaccc tgtgctctct gaaacatgtg 43260 ctgtgtccac tcagggttaa atggattaag ggcggtgcaa gatgtgcttt gctaaacaga 43320 tgcttgaagg cagcaggctc gttaagagtc atcaccactc cctaatctca agtacccagg 43380 gacacaaaca ctgcggaagg ccgcagggtc ctctgcctag gaaaaccaga gacctttgtt 43440 cacttgttta tctgctgacc ttccctccac tattgtcctg tgaccctgcc aaatccccct 43500 ctgcgagaaa cacccaagaa tgatcaatta aaaaaaaaaa aaaaaaaaca acccaagact 43560 gcataaatgt ccattctgaa aacttggaag aagtaccacc ttgatgaata agctgtctag 43620 cttttattgg catttaagta ttctgccata gggaagtgta aaagttgtag gcttttactt 43680 tttataggta ctatattgtc caaataatct cagcacctca tggttgctaa ggatctgtgt 43740 ccttgtttgg tcagattatg tttatctctg gcataaggca cttaacaata ttcattaaag 43800 gttacagaat ctttttgctt catctgctta gcatttcata ccagtttgtt ttccaccaaa 43860 ctttcaaatt ttgattgttt cattaatatt ctgcatactg atgtaaacca agttctatta 43920 ttgtgcaatc tgctcctgaa acccttagga actctctgaa ggagttttat ttattttttg 43980 tttttgtttt tgtttttgtt ttgttttttt gagacggagt cttgctctgt tgcccaggct 44040 agagtgcagt ggtgcgatct cggctctctg caaactcggc ctccggggtt cacgccattc 44100 tcctgcctca gccaccggag tagctgggac tacaggcacc caccactgcg cctggctaat 44160 tttttttgta tttttagtag agacggggtt tcaccgtgtt agccaggatg gtctcgatct 44220 cctgaccttg taatccgccc gcctcgcctc ccaaagtgct gggattacag gcgtgagcca 44280 ctgtgcccgg cctttttttt ttttttttct ttatgggctt gtcttctaca cttcagattt 44340 gactaaatta aatatgcatt aaatgaagtc aggagttcac attgccacta gtaacaatgc 44400 ctaagcttac ataaagcatt ataaaattgt tggtgattag tgccttctca gctatgagta 44460 taagataata ttatactagt agttcagttg cctagataaa ttgtacacta tgtgaagttt 44520 tatttacata attcttacgg tattttttaa ggtagttgat aacagttgag actacaattg 44580 tatctccatt ttattgatag taaaatgaag gaagggaggg ttactaccat aggagagctc 44640 ctccccgttg cactcttgcc tgtaaaaatt tttctgccaa aacaatttag ataatagaat 44700 tgtaaaaata ttattataga attgtttctc tcaaactata gtaatgtaga ataggttgaa 44760 ggggtgatga tttgaaacaa tacctctcca ttagctaaat tttatataga atctattgca 44820 tgttttaaat gataagtcag atttataaaa atatttttat aaacagtagg aaatgagttt 44880 aggggtattc acatacagtt ttaattttta tttacatatt taaaacatat catggtataa 44940 atatgatgtg gatataaatt tgagataaag gaagtattgt ttaagaattg atgaactaat 45000 ttcttaaaag atgtcatcac cagttggttt tctagcctta tgaaaaatgg ttgcaataaa 45060 aaagattgac tatgataaaa tgctgccctt tcattttaac ctagaccaag agaaaacata 45120 ctgtgaatct atgatgaatg aaagaaagtt gtaactgttg gttttgtata tttgtaatta 45180 ctgtttattt tcatttcttg tgaactgata ctgtactttg ttcattgtga gtagacaact 45240 tataatctat gtactcaaat tggtttagta taaattctag ggaatgaagt tcatattaac 45300 tgtaaaataa catgattgtt ctctaaaaca aaacgtcttc tgggattatt tttaactaag 45360 gcgcatgggg atcttttttt catttttaca gggaattgac ataggggata gcttaactat 45420 tccagatgaa ttcacggaag acgaaaaaaa atccggacaa tggtggaggc agcttttggc 45480 aggaggcatt gctggtgctg tctctcgaac aagcactgcc cctttggacc gtctgaaaat 45540 catgatgcag gtgagcttta ttatcgtgtg tccaggtttg ccctaaatat tctaaaacaa 45600 tgagaaatgt ggtgctttga aaaagaagtt ttaaaatttc tcagtaataa tcttttatac 45660 cctaaaaaat aaatctattt tgttgctgtt aactctaaat tcagtccatg taagtatggc 45720 agtgtaccaa accttaaatt gttagtacat gtgtgtaatg aacttttaat ctttggcatt 45780 ctatgactat tcaaacattt aattcaaaaa atatctctag ctattgttgt aggattctcc 45840 tgatttatag tttccttctt tttaatatac tttatcaaaa gtaaagtatt tttgaaatct 45900 agactcttag agcagcaatg taattttgaa aattattcta aagctgaggt tagcagaaaa 45960 agatctggct ttatagactg actttgctat ttactagcag tgtagcattg ggctggccag 46020 agtggaaaga gggaatggaa aagaattaat atgtatttgc tcactgtggt aacccagtta 46080 atccttgcag cagcccagtg aagtaggtat tttatcattt ttccaggggg aatctgaggc 46140 ccagagaatt gacttttcct ttacaacaaa tgagaggggg aatgcagtat ctttgcctcc 46200 agtgctcctg gttctcatgc tgcatgaaac ctctgaggtc tcattttcct tcattctggg 46260 atggggataa gaatatctaa taagaatggt ttaagaatca agcaatatca ggtatgtgat 46320 aatgtctggt acactggaat aacctattgg aacatagtag ttgtttacaa aatattttta 46380 aaactttgtt atacttatgg tcaacacttt ttatatttgt ctgtagattt ctgtacaaaa 46440 agattctgac actgttttaa gccagcattc cttcagaatg tacccaaatc tcaaaattta 46500 tttaggggca aagctaatgc tttaaagaaa aaggagaggg gattggtgtg tgtttttctt 46560 taggaacagt agtaacttga cttttagaga acttgaataa gcatttattt tttcctttgt 46620 cctattttat tgtgaagttt atttatttaa aataaaatgg atttctctgg aatttagttt 46680 ctgcaaattt gaggagtttc caaagtcaac cttcaggttt gatacttctc tagaaagact 46740 cacataactc actgaaagct tattacccct ggttatggtt tattacgggg aaaagatgcg 46800 gatgaaaatc agtcaagtaa agaagcacat agggcagagc ttctgttgtc ctctccctgt 46860 ggagtctcca tgtcttactt tcctggcact gttatgtggc actaggcatg gaatattgca 46920 gaccaaccag ggaagctcac ctgagccttt ggtgtgcaga gttcttattg gggcctgttt 46980 tcatactggc cacatggctg gccttcagaa ttcaacccgt tctgtgagtg tgtgtgtgtg 47040 tgtgtgtgtg tgtgtgtgtg tgtttagtgg tagtcacccc ttttatgtga gctgaaacaa 47100 tcagaagaat agctgatttg tttaattatt tttggtgtat tggacttaat cagtttttat 47160 ctgtaggtgg tcataaggta cagtattttt aagtgactac cacatctgta gtataagcca 47220 agtaatttat cagtactcac aggatgggta catgttgtaa tgaatttatt gcctagagag 47280 ggcctcaaaa tatgccaaag agggtgcaat ttttattttt ggtttcaggc tgtatgcatt 47340 ccagtgttgg tagccctgat atacacaata tccaaaccat ttcagaccca tttacagttc 47400 atgtctgtac tacttcttga ggagagggag taacatatta ctttaaatta tatgtaataa 47460 tatacataca ttaaattata tgtaataata taatattatt atttgcagta tactttttta 47520 tttcccttta actgagcttg ttcatgtttc aaagggtgtt ccattgcctg atacataatt 47580 tagttaatat tatcttatga aggttgttca taattttaat actcttcttg tcttctctct 47640 ctgctttctc acactgaaga taccaattat tcttagtttt agagtcagag acaggcctct 47700 aaaatcatgg caatactccc tctcatcatt atatatattt ttcaaccttt ctatatttta 47760 ttttcaaata tatcttcttg cagttagaaa cggtattgaa aaagattgtg tggttgttct 47820 agaaaaagta atagtaatat gccaccagca ttttatatca ttctgctttt atttttaggt 47880 tcacggttca aaatcagaca aaatgaacat atttggtggc tttcgacaga tggtaaaaga 47940 aggaggtatc cgctcgcttt ggaggggaaa tggtacaaac gtcatcaaaa ttgctcctga 48000 gacagctgtt aaattctggg catatgaaca ggtaattgtt atcacccgtg gaatttatta 48060 acaaagagga gttagtaaac ggattcaata aatgttaatg tataatgctt ttgggattct 48120 tgttttaata catgataatc tttcacatat accccataag gaggatcact tataggagat 48180 tagactaaat aaaatcagag atttctcatg accaagttat gggattctta attcatcata 48240 ttatttataa agtttttttt ttctaagtag ttcttaaagg aagggtagaa ttttagttta 48300 ttcattctga atcctgagca gaagcagcac actaacataa gttttatgaa agtgtcacaa 48360 tctaacctct ggaaggaaaa ctataagttg aagtcctttg tgtaatttga cgttgctgta 48420 aaattgagct gagtttggag tgacacctcc atgaaggcag gggcgtggct tcttccccat 48480 gtactccagc acctagacag agcttggcat gtgataagtt tcaagcgagt gttgaatgag 48540 tcaatgaatg aacaaatgca tttacctctg aatcacttct ctgtcggctt ttgttaactt 48600 ggattatttg agctattgct tcagcctaac tcaatgtaaa ggggaaatac agaggtaagt 48660 tttagagttt gggttctctt tatggtcatt agcagaactg tctagttgag cagccacaga 48720 ttatgttttc cattatttat tccatcattg tttatcaagg actgtaaggg ccttgaaatt 48780 caactccccc ccccatagtt tttgtattat tccatgtaga ttttagatta ttctggagag 48840 tgttttgttc ttgagcaaca gaatactctt gagaagatta cgaagtccag tggtatcctt 48900 ttctttgcct aggaaataga gaagcaaaaa aaaaaaaaaa aaaaaattaa agaaaatcta 48960 gtctccagga ttttaattag aacctatcct tgggaaggct attttcctta tatgaaggtt 49020 tgaagattca aatcatgatt attaagggct aatgtttgag atacccttag gttattctga 49080 ccacatactt ggattttatg ataggaaagc cacagcctaa aataaataaa tactcaatgc 49140 agttatttca gtatgcaaga agtttggtat ttttgaaaaa gtccatgggt attgcaagca 49200 aatatgcaca ttttgcttta tgccatttgt cagattctta ccttggatac caccaacagg 49260 catcctctgc ttctgtccac ccaagctcct tcctgagacc tctttatagt attgtgattt 49320 ctgcacacta actttcttag acatgaagag aaagctgtct acacagtgtg gtgtagtttt 49380 cttatgggct ctggacctat ggtgctgttt tctctcctcc tgctgaaggt ccattcatcc 49440 ctcggggctc tctaaaagcc accttcctgt gacaagcata tactaagcat ctcaatcaaa 49500 gccagttcct cccctgtcca gcctccctcg agtgctgaat tgcagaatat cccatttttc 49560 attggatgat ggaaaaccca ttgttttccc agtggattgt aaattacttc ggggtaaata 49620 ggctgtatat attctcaaat ttcccagagt atgtaactag gtcactttta gattcagata 49680 gattttgttc cttgaatagc tagtacttta ggaaactaag aaaaagatct tttcaacctg 49740 gtatgtagct ctgtcaaaca catcatcagt atggggtaaa cctgtgttct ctgtgggttg 49800 tcattaccat agtagtgtca ttgtatcatt gacagtgtaa tagtgtgggg tagtgttctt 49860 gtggtttcag ctgccactct gtactgactg ctttccactc caacatcttc ctctttatct 49920 caacactgta ggtctacctg tgtactgtgt gtttcagcat ctctgcttgc atgacccagg 49980 agtgcctccc actcaatatg gccaccatgc atggtcatct ttctgctact ccctgtctcc 50040 tgaccctgct ccagcaacac agacagacac ccttcctctt tctatatgtc atatggtggg 50100 gaatgccctt tagtacttac tcaggagtta gttcctctgg gaagccttct gttctagttt 50160 ccttttgtta cagcactttc acattgaatt ctgacgttct ctgtacttat ctgctttgtg 50220 agactgtgag cttccttagg cagtagctac ttgtattctt agcaccttgc ccagtgccag 50280 gaaaccctta ttaagtaaat gaaaagacag aactgacaga ctggaattag agctcaagct 50340 tgcctcaatc tcaagccatt aagatgaagg ggagccgggc gtggtggctc acgcctctaa 50400 tcccagcact ttaggaggta gtttgcttga gcccaggagt tcaagaccag cctgggcaac 50460 gtggcaaaac cccatttcta caaaaaatat aaaaattagt tggacgtggg ggtgtgtgcc 50520 tgtactcagg atgctgaggt gggaggatca cttgagctcg agaggcagag gttgcagtga 50580 gctgggatca caccattgca atctagcctg ggtgatagaa tgagaccttg tctcaaaaaa 50640 aaaataaata aataaataaa ggggaagata aggattggaa acagaaggag cagcatgtgg 50700 acagaaatgt aggcacaaga aggcatcact cactgaagag actgaaagtg gttcactgtg 50760 cctcaagact ggtggagtgt gtttccggaa agataatgat gaaagagctg gacagataaa 50820 caggggccaa atgtaatagg agtctggatt ttattctgaa tatggtaggg gctattgtag 50880 catcttatat agggaagtga aatgagtaca ttcacattta aggaatatca acctgaaaaa 50940 agagtggaga cattgttggg ggagagtgag gtagactaga ggcagggaga atatttaaat 51000 aattgaggta agaaatgatg aacaccagta taaggtgatg tctttaagga atggagaagg 51060 gaatgaactg agaaatattt tggaagtaga atcaacagaa ctcactgact gactggatat 51120 ggaggtgaga aagagaagag tcaagaatga tattctaatt tctaacttga gtgactgcat 51180 tcaaagagaa tacaatatca ggttccattt tgtgcatgct gagtttgaga tgtgtgggac 51240 atgtacaggg agctgtccag taagcaattg ggtatatcag ctagccatta agagagagat 51300 ctttgataga gaggttgttg ctgagttgag ccattggaat gggcaggatc actcaagaag 51360 agcttataaa tgagaagaat tctaggaata agtccaaagg gagaagtaaa agaagaaact 51420 tgcaaaggac actgagaaga aatagctcga gggatgggag aaaatccaga gagagggatg 51480 gcataggagt cagtggaagg aaacggtttc atgggggtca gtactactgg gtagtgaata 51540 taataagaat atcttttagg atttctcaac ccagagatag gtaagcttag tataaatgct 51600 tctgtgaagt aatgaaatga gaaaccatgc tgaaatgagc ttaaagtgaa tgggaggtga 51660 agaaacttgg acagtagaga cacattttta gggagtttga cagtgaagag aaggaaacta 51720 gaagagggag agggtgatag ataagaaaga tgttgggtgg aggggatttg tttttttgtt 51780 tttttgtttt ttttctgttt gtatgtttgt ttgtttttga gatggagtct cactttatca 51840 cccaggctgg agtaaagtgg tgcaatctca tctcactgca acctctgcct cctaggttca 51900 agtgattctt ctgcctcaac ctcctgagta gttnnnnnnn nnnnnnnnnn nnnnnnnnnn 51960 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 52020 nnnnntgcct cagcctcccg aaatgctggg attgcaggag tgagcccccc gtgcctggcc 52080 tggagggagg attttgattt gactttaatg tgcctgttgc tgaaggaagc atgtcaatac 52140 aaataaagaa gttgaaaaca taggtaagag aggttgatta acccggtagg tgtttcaagg 52200 gagtttgtgt gtagggaaag ggagtgggag atggaaaggg gctgggggag acaggttcta 52260 tccagagact gttaaaagga ttagtctttg attacaagaa gaactcttct tatacgtgtt 52320 tgggaagaaa aaatatgtga gtagctatgg ataattttgc aggaggtggg cagaatacca 52380 agatattctg cctggtggcc tctctactct tccttgagct cctgagaaag gatgtgatct 52440 gagaatgagg gaggaagtgg tattggaagc tggaggagaa tggagaagat caaaatggtt 52500 agtctaacaa atgggagaga actgagatag acaaaaggat ttcagggtgg ttttgagggc 52560 tcagttaagt ctcctttagg aaggttcagt tctgtagcct tggcaagtta cttaaagtct 52620 ctgtgactat tacctcatct ctaagatggg gactaagctt ggtgacatag ttttacatac 52680 caggcacagt gcctgacttt ttggctctgt cctgaagtct tccctttgta tatggtatgt 52740 ttcggggaat aggagcctca agcacttatc ctttaaatat ttatcctcca tcagtcacta 52800 aacgtttact ctgtactttt gataggtgct gtgggggtcc agggtataaa aggtaccttc 52860 aaagttactg ttaaagtgca ggaaggtttt taagcaaatt atgtttaatg attttgacaa 52920 tctgacatgc aggaaaatta atagggccta tgcagaagag gagttttatg taacactctg 52980 tagttcagga aacagagccc ttggaagcag tgatctctct ggggaggaat gtctggtatt 53040 tgggaatctc atgaaatgat aatatactta atttttatca tgagcagcaa aacacagatt 53100 tgctaggaga aagtcatcgt atgttgttgc attgggcact ttagatccca gggaacagaa 53160 actggctggc acaggaatgg gcatcactgt ggggatggat catgtagggg aaggatccct 53220 ggagaagtcc aggaggtgag acttccccct tcccttctcc atgcatgagt ccacttctct 53280 ctgttgactt tccccttgtc cctctggtga cagcagctgc ttacctctgg agaccccctc 53340 acatttctga gagaaggaat ctggcttgcc tggctaattc ccatggtcta tgtttgggca 53400 gaatgtctta gcaagttgtg taaagatagt gtattcatat attaataata ataataacat 53460 ctactgaaca tttgctaggt gttcagacct gcactaaccg tgttacaagt attatttttt 53520 tgtaatcctt tccataaccc tgtgaggtaa gtactgttat cacagacaag gaaaccacaa 53580 tgtggacctg ttcatgaact tgctcgaggc cacgtggctc tggagttcca gctcaggtct 53640 gcctgactct caatcccatg atattaatat actggccagt cactattttg gctgtattgg 53700 ggtcatattt atacccttgg tccagttagc tatgttgggt cactttagta ctgatagcca 53760 gggagatgct gggcttgata ggttagtata attctatgta ttacctacaa aaactgtttt 53820 tataaattgt tttgttaaca tttgtttgtc acctatttat tcattttatt tgcactggtg 53880 aaaataaact catcttttaa aaactgtggg gaaaatatcc aaacattgtg aaaacttgat 53940 taaccttgta ttttctgtac acctggggag ggatgctgtt atgctgtttc agcaaaggag 54000 caacttggtc caatctggga gacatctgtg ttttgtggaa atctgacttg aaaaccactg 54060 tccagtcact gcgtgtatta gcatttaggc cttgctcttc tgctatgtat tattaatgta 54120 gtgtatacat ttcgagacac atcatcacat ttgtcaattt attgatttct aggagctgat 54180 ttgtattcta ggattgtcta gttggcttgg gctgccataa aataccacag tgtgtgtgga 54240 atcaacaacg gaaatttatt tctaacagtt tcagaggcgg gaaagcctaa gatcaagggc 54300 caagccagtt tgatttctag tgagcgttct cttctcagct tgtagacagc tggtatgtgc 54360 tcacatggtc ttttcttggt gcacatgtga agggggagag agagagtggg ctctctggtg 54420 tctgctctta caagaacact gatcctgtca tgagggctcc atcctcatga cctcataacc 54480 ctaattacct ccagaagcct catctcctaa taccatcaca tgggaggtta cagcttcaac 54540 atatgaattt ggtgggggtg cagctcagtc cacagcaggt agtaatgtgc attttaaaac 54600 ttgtttatac agtacaagaa gttacttact gaagaaggac aaaaaatagg aacatttgag 54660 agatttattt ctggttccat ggctggagca actgcacaga cttttatata tccaatggag 54720 gtgagtacca ttgtcaagtc tgactgtgtg atggtgttcg tgttggttgt ctattgctct 54780 ctaacaagtt atcccaaaat taacagttta aaacaagcat ttatcatcgc acagtttctc 54840 tgggtcagga atctggaagc agcttagctg ggtgcctctg gctcagggtt tttcacagcc 54900 cacagtcaag atggtagtca gagcttggaa tcagctggag gcggattcca agctcactca 54960 tgttgctgcc aggcctcact ggctattggc tggaaacatc agttccttat cacgtgagcc 55020 tttctgtagg ctgcctgagt atcctcaaaa cacagtagct ggcttcccta gagtcagtgg 55080 tccaacagag agagagagag agagtgccta agatgaaagc tggtatcttt tgcctcttct 55140 gctgtattcc attgatcaca cagaccaacc ctggtagagt gtaggagggg ctggtataat 55200 ggtgttaata accggagaca aatatcactg ggggtcactt tagaggctgg ctgccacttt 55260 agaggctggc tgccattcct gtccaaagag tttctgtacc ataaatttaa taatggaatc 55320 tcaggatttg attatatggt gattatccta attagacatc ctttcattag tgcataggtt 55380 ggcaaaacac agacctacgg actgtttcat acagcccttg acctaagaat gccttttaca 55440 tttttaaaaa gtgggcaaca caggaaaaag tgagaaagat ctaaaatcga caccctaaga 55500 tcacaattaa aagaactaga gaagcaagag caaacaaatt caaaagatag cggaagacaa 55560 gaagtagcta aggtcagagc agaactgaag gagatagaga cacgaaaaac ccttccaaaa 55620 atcattgaat ccaggagctg tttttatgaa aagtttaaca aaatagacaa ctagccagaa 55680 taataaagaa gaaaccagag gagaatcaaa tagccccaat aaaaaatgat aaaggggata 55740 tcaccaccaa tcccacagaa atacaaacta ccatcaggga atactataaa cacctctatg 55800 caaataaact agaaaatcta gaagaaatgg ataaattcct ggacacatac acgctcccaa 55860 gactaaatca ggaagaagct gaatccctgt atagaccaat aacatgttct gaaattgagg 55920 cagtaattaa tagcctacca accaaaaaaa acccaggacc agacagattc atagccgaat 55980 tctaccagag gtacaaagag gagctgatgc cattccttct gaaattattc aaacaataga 56040 aaaagagaga ttcctcccta actcatttta tgagggcagc atcattctga tactaaaacc 56100 tggcagagac acaaccaaaa tagaaaattt caggccaata tccctgatga acatcaatgt 56160 gaaaatcctc aataaaatac tggcaaactg aatgcagcag gacatccaaa agtttatcca 56220 ccatgatcaa gttggcttca tccctgggat gcaaggctgt tcaacatatg caaatcaata 56280 taacggaatt catcaataaa cagaaccagt gacaaaaacc gcatgattat ctcaatagat 56340 gcagaaaagg ccttcgataa aattcaacac cacttcatgt taaaaactct cactaaacta 56400 gttattgatg gaatgtataa caaaataata agagctgttt atgacaaacc cacagccaat 56460 atcatactga atgggcaaaa gctggaagca ttccctttga aaaccggcac aagacaagga 56520 tgtcctctgt cagcactcct attcaacgta gtattggaag ttctggccaa ggcaatcagg 56580 caggagaaag aaataaagcg tattcagata ggaaaagagg aagtcaaatt gtctctgttt 56640 gcagttgaca tgattgtata tttagaaaac ctccttgtct cagccccaaa tctccttaag 56700 ctgataagca acttaaagca aagtctcagg gtacaaaatc aatgtgcaaa aatcactagc 56760 attcctatta accaataata cacaaacaga gagccaaatc acgagtgaac tcccatccac 56820 aattgctaca aagagaataa aatacctcgg aatacaactt acaagggatg tgaaggacct 56880 gttcaaggag aactacaaac cactcctcaa ggaaataaga gaggacacaa acaaatggaa 56940 aaacatttca tgctcatgga taggaagaat caatatcata tcataggaag aatcagtggc 57000 catactgccc aaagtaattt atagattcaa tgatatcccc atcaagctaa cattgaattt 57060 cttcacagaa atagaaaaaa ctaccttaaa tttcatatga aactaaaaaa gagcctgtat 57120 agccaagaca atcctaagca aaatgaacga agctggaggc atcacgctac ctgacttcaa 57180 acatactaca aggctacagt aaccaaaaca gcatggtact ggtaccaaac agatatatag 57240 accaatggaa cagaacagag gcctcagaaa taacaccaca cgtctacaac catctgatct 57300 ttgacaaaaa caagcaatgg ggaaaggatt ccttatttaa tgtatggtgt tgggaaaact 57360 ggctagccat atgcagaaaa ctgaaactgg accccttcct tacaccttat aaaaaaaaaa 57420 ttaactcaag atagattaaa gtcttaaaca tagacttaaa ctataaaatc cctagaaaaa 57480 aaccgaggca ataccattca ggacacaggc atggacaaag acttcatgac tgaatcacaa 57540 aagcaatggc aacaaaagcc aaaattgaca aatgggatct aattaaacta aagatcttct 57600 gcacagcaaa agaaactatc atcagagtga accggcaacc tacagaatgg gagaaaaatt 57660 ttgcaatcta tccatctgac aaagggctaa tatccagaat ctataaggaa cttaagcaaa 57720 tttacaagaa aaaaaaaccc accaaaaagt gggtgacgga tatgaacaga cacttctcat 57780 aagaagacat ttatgcagcc aacaaacgtg agaaaaggct catcatccct ggttgttaga 57840 gaaatgcaaa tcaaaacccc aatggcatac catctcacgc cagttagtta aaaagtcagg 57900 aaacaacaga tgctggcaaa tatgtggaga aataggaatg cttttacact gttggtggga 57960 gtgtaaatta gttcaagcat tgtggaagac agtgtggcaa ttcctcaagg atctagaacc 58020 agaaataccg tttgacccag caatcccatt gctggttata tactcaaagg attatagatt 58080 tttctactat aaagacacat gcacacgtat atttattgca gcactgttca caatagcaaa 58140 gacttggaac caacccaaat gcccatcagt gatagactag ataaacaaaa tatggcacat 58200 atacaccatg gaatactatg cagccataaa caaggatgag ttcatgtcct ttgtagggac 58260 atggatgaag ctggaagcca tcattctcag caacctaaca caggaacaga aaaccaaaca 58320 ccacatgttc tcactcataa gttggagttg aacaatgaga atacatggac acagggaggg 58380 gaacatcaca cactggggcc tttttgggga tgaggggcta ggggaggaat agcattagaa 58440 gaaataccta atgtaggtga caggttgatg ggtgcagcaa accaccatgg cacgtgtata 58500 cctatgtaac aaacctgcac gttctgcaca tgtatcccag aacttaaagt acaattttta 58560 aaaagtaggc aaaaacaaaa gaaaagaaaa gtaatataca accgagacct aatattttag 58620 gcttgcaacg acagatattt tactatttag tctttacagg aaaagttttc caactactgc 58680 tttatagcaa aaataatatt gtagatgtgg aatttattga tatagcagag gggtttttag 58740 taactgatga cttaagcaag ataaatacaa ttttcaccga tatgtggtat gcatgctaat 58800 acagcttttt ttaagcatct taatatgatt gtttatatta ctccacacac ctctcaaaaa 58860 aacttaatac cctatttttc ctctcatatc ctcccatatc agttaatagt atcaccttcc 58920 caactcccca ctgccccatc ctgtgttcca agctagaagt attggggtta tcctttatac 58980 taccatttcc ctcaccttcc agatgcaggt ggtcaccagt cagttttgtt aagacatcaa 59040 tagattatct tgcttccatt tccttggtca cttccttcat cagatcctcc ttgcagtaaa 59100 cgggtctctc tggctttggt cttagccccc caatagaggt aatacatgaa agagaatgta 59160 tcaacaaatt gtacagtctt ttgagtgaca atatgtgcta ggtatttgtt ccatgtaaaa 59220 ttacttcatt tgaatcccat gatgatagag ttaatatgaa caatcatatt ttgttttttt 59280 ttatatccag gttatgaaaa ccaggctggc tgtaggcaaa actgggcagt actctggaat 59340 atatgattgt gccaagaaga ttttgaaaca tgaaggcttg ggagcttttt acaaaggcta 59400 tgttcccaat ttattaggta tcatacctta tgcaggcata gatcttgctg tgtatgaggt 59460 gagtttgtag aaatcttttg aattggaaaa tgcagttaga tcttgttaga attggacttt 59520 atatgaagaa gtagatatat accagaaaac agtgtgtgac cagaagtaaa ttcaagcatg 59580 tgttatttga actttcaagt aacttgagtg tgaatatgca tggggtcact tttgtattag 59640 attttcttgg gaattgcttt tgttaatgaa gagtagactc aaagttaggt atagttgttc 59700 accttaaaag gtgtttctag agattttttc ctttgttttg gatttgcaaa aatctgacat 59760 taagccaagt gactaatgtg actaacatga gtaatacagt ttcattcctt gtacggaaga 59820 atacaaatct tggatcaacc ctgcaatcta aatcatttaa taatttatga atctcacaaa 59880 caattattga gcacacacta tacaaaccac taggttagac actggatctg gggattcaaa 59940 ggactcaatg tgtgccttga agaaactgaa ggtctggtgg gggagacaaa cgactaaaac 60000 tcagcgtggt tatctgtgct gcgacagaca tgagccaggg tgcatgttag gatgagacct 60060 aagctacagc gtagaggaag agtggaatgt gtaatgaaaa gaagagtcga attttttttt 60120 taaagagctt tattgagatt tagttcatat tccttacatt tcactcattt gaagtgtaca 60180 agcaaatggt ttttggcttc ttacataatt tttaaaaatt attataaaat ataaaatttg 60240 ccattttact aattttaagt gtacaattca gtggcattaa ttacattcac aatattgtgc 60300 aaccatcaac actatttcca aatccttttc ctcactccaa acagaaacac cttaaccttt 60360 aagcaataac ttcctaccct ccgtaactca aacctttggt aacctctaat ctgctttcta 60420 tgtctaggaa tttacccatt caagatatct tataagtaga atcatacagt atttttcttt 60480 ttgtgtctga tttattactc ttagcataat gtctctaagg tttgttcatg ttgtagcatg 60540 tatcagaact tcatttcttt tcatggctga gtaatattcc gttatgtgta tataccacat 60600 tttgtttagt ccttcatctg ttgaagagca tttggattat ttctactttt ccaacattgt 60660 gaataatgct gcagtgaaca ttggcatctg cgtatctgtt cgagtctatg ccttcaattc 60720 ctttgggtat atatctcaga atggaattgc tgagccatat ggtcattctg tgtttagctt 60780 ttaggaacta tgagactgtt ttccatagtg gctgcactta cattctcacc agcaacatac 60840 aaaggttcca gtttttccac gtccttatta acacttaatt tccattttaa aaaagcttat 60900 ttttattatg gccgtcctct taggtgtgag gtggtatggt tcaggacttt acttcttgtg 60960 ctgagttttt taaaaaattg tgattaaaaa cacataacat aaagtttatg attttaacca 61020 tttttaaata tatagtacag taagtgttaa ctgtttgtgg tttgttgtgc aacagatctc 61080 tagaactttt tcacttctca aaacttaaac tctatagtca ttaaacaaca gctcccaatt 61140 tccccttcac cccagcgctg tgtaacctac tttctcgttt tatgagtttg actacattaa 61200 ataccttgta taagtgaaat catgtggtat ttctctttcc gtgactggct tatttcatgt 61260 aacatagttt cctcatgatt catccatatg atagcataca acaggacttt tttgttttta 61320 aggctgaata ataatttgtt gggtatatat atcacatttt ctttattcat ctgttgatgg 61380 acatttggat tgtttctaca tcttgactat tgtgaatagt gctgcagtga acatggttgt 61440 gcaaatatct cttcaagata ctgttttcag ttctttttga catatactca gaagtggaat 61500 ttctgggtca aatggtaatt ctatttttaa gtttttgagg aacctccatg tcattttcca 61560 tagtaactag acctttttgt tttttaacat ttctatcaat gtacaccaag attccaattt 61620 ctccatgtcc tccccaacac cattaagtgg ggtggtggtc tactactatt gctgtgttgc 61680 tgtttattcc tcccttcagt tctgtaagtg tttgcttcat atatttagga gcttaatatt 61740 aggtccatat gaagttataa tttcttcctg gtaaagtgac ccatttatca ttatgtaatg 61800 tccatctttg tctcttgtga cagtttgtgt cttaaaatct attttgtctg atgtaattat 61860 ggccacccct tttctctttg ggttcccgtt tttatggaat atctttttcc atcctttcac 61920 tttcagctta tgtgtgtcct tagatctaaa gtgagtctca tagataaggt atagttgatt 61980 ctgtatgtgt tattcactca gcaatttata tcttttagtt aggggattta atccatttac 62040 atttaaagca gttactgata gggaaggact tactgttgtc atttggctag ctaccttttt 62100 atctttgtcc tgtggctttt ctgtttttcc cttcctctct tcctggcttc ttctgtgttt 62160 tgttgatttt tttttttttt gtagtgatat gttctgattc ccttctcatt tccctttgtg 62220 tgcattctat agatgctatt tttgtggtta ccattgcaac tacataaagc atactaaagt 62280 tatagcaact tattttaagc tgtttacaac ttaacttcag tggtatataa aactctattt 62340 ctttacatat ttcacctcct ccccacaaac tttatgtctt ttgatattgt atatccttaa 62400 catagattta tagttacttt ttatgctttt cttctttaaa ttctgtttaa attttgtttt 62460 tgaaatttag attttcaagt tatttatata ccttcattac aatactatag gattttataa 62520 tattctaaat attgaccttt accatagagt ttcatatttt gtggttttgt gttgctattt 62580 atcatccttt tgtttctcct tttagccttt cttgtagggc cggtctagtg gtgataagct 62640 gtatcagctt ttgtttgtca gggacagtct taatttctcc ttttttgaag ggcagttttg 62700 cccatacagt atttttgttt ggcagttttt ttaagtttca aaacatagaa tataacattc 62760 catttccttc taacctgcaa gatttccatt gagaaatgca ctcaatggat tttttaatcc 62820 attgagataa ttttttaatc ctgtaggatt taaaattttt agtcttacag gattaaaaaa 62880 ttaaaaagtt aaacttgtta tataacatat taacatgtat tttatactta aagtatctta 62940 tgtttaaaaa gttgattatc atatatattt tatacagttt ctcctaatta ttgccttcta 63000 atgaaataca gggacctaga gtaacaggga taaagtatgg ccttttgatc agcacgcctg 63060 gttctgagtc cttcttaaaa aaactctggg cctggtgtgg tggctcatgc ctataatctc 63120 agcactttgg gaggccgagg cgggcggatc acctgaggtc aggagtttga gatcagcctt 63180 gccagcatgg tgaaaccctg tctctactaa cagtacaaag attagctggg cgtggtggtg 63240 ggtgcctgta atccaagcta ctcaggaggc tgaggcagaa gaatcgtttg aacctgggag 63300 gcagagattg ggccactgca ctacagcctg ggtgacaaga gcgagactcc atctcaaaaa 63360 aacaaacaaa aactccgctg agatgaattt ttctcatttc taaaatcaga ataatagatt 63420 tatgtaagag tttctgtaag gctcaaatga aatatatgta acgtgtaaaa tgagatacaa 63480 ttagtagaat tatattattt tattaatact caccataaga ggtgttcttt agatcctgca 63540 gcgtttgctg cgcagttcac gtttgtttag aagaatgtca gtaaccggtg caaacctcat 63600 gtgttccgca cccccagtgg cctcccacct ctccacagag tcaccgcctc ctgcagtgcc 63660 tgctgcttct gcaaatgcgt ggcctcatcc tgcagaaacg gggcttctca tgaggttgag 63720 aatagctgtg aaaatgttta cgttgaagtt gtagagttcg ttaattattt tcttctttat 63780 ttctctggca gctcttgaag tcctattggc tggataattt tgcaaaagat tctgtaaacc 63840 ctggagtcat ggtgttgctg ggatgcggtg ccttatccag cacctgtggt cagctggcca 63900 gctacccatt ggctttggtg agaactcgca tgcaggctca aggtgaattt ttgattacag 63960 aaccacaccg ataaaagtgc tgcaccagta atgtgctttt agaactccaa gttctactaa 64020 gatgcagact gtagttttaa gacagtattt ctcaaccttt ttttcattat tgcctcctta 64080 aggaatcttt tcagaaattc tttttctaaa tgctccctcg tcatgaaatt ttaatgcgac 64140 agaagcattg catatgtact gtatgcatac atatgcctta tagataaaca gagtactatt 64200 ttttttgact gtgttacatg cacgttttaa gattataagc tttagtatct gatggatttg 64260 ggttcagatc cttgcctcag acttcttggg gtttttaatg ggaatgaaaa ttgtacagtg 64320 ttgtaagaat taccaacaat ataaataaag catcttgggt ttgttaaatt tttggtaaat 64380 ggtggttgga atcatttttt agtgttgcgt agaccctaca agttttgagc tgtgattcct 64440 cctcactgtg acactgtctc cattgttggc tttgattaca ctgtaccatc ctggttgttc 64500 tgccagccca ttgataactt ttaccatttg ctggctttta ttgctatccc cactctatta 64560 aagtatgcat tcaaatgcct ttcttttctc tttgatgctt tccctggtca gtcttatcca 64620 ttgttttctt aagtagtaca ccttgggcat ctacagctct attcccaacc tcccttccaa 64680 gtgccagcca cagcaacccc agccaagcag tcagtaacta attggcaaat actccctgag 64740 ccattgtccc attctagaca ctgccagatg ctaggggtag agcagtcaac aagtcaggtg 64800 tggccccgcc agtgtagagt agagaagacg ttatgtccag caagtaaaca acctggttaa 64860 accaactcct cttttgttag gggagcacag agcaaggagc tataacctaa cttgggcgct 64920 gcagaatgct gtcagtgaag ctgagactgg aaagatgagt gggagttagc tgggcacagg 64980 ccagtggagt gggaacagaa aacattccag ttgagggaaa gcatgtgtga agacactgag 65040 gcaggcacca acatggtgta tttaaggagc tgagagacag tcatggctgt agagaaaaac 65100 acaaagtagt gaactacacg tttcttgtgt attctctcat ttcaccatca taaccatctt 65160 ggggatggga atactaacat tatccccatt tttcagatga gcaactgggg cagagagaat 65220 ttaagtaact cccacaagat tatacctgtg gtaaatagtg ggactgaaat tcagacacat 65280 gcagtctgat tctaaccctc ctgtctgcca gctctgatcc agaactttgc atgactgata 65340 cggctgatag attgtctatg gctgatagac tgtcatttct gacctaaaag tctgatcatt 65400 ttacatctgt tcagacatct ttgcagcctt tcggtgtcag ttccaaagtt gttagtggga 65460 atttcaaagc ctttaataat ctagccccac tttgttcact ctctgtgtaa taaccacata 65520 caacaattgg ctgcatctcc atagcacatg gtactcctcc cgttgtcttg gttgtgccag 65580 caacactggt tttcgctttc tcttcctgct tgttgaggtc atttccaagg cccaggtctt 65640 tgtgcttttt cccaagcttc ccagagcttc ttccatactc cccttacttc ctgagattta 65700 actgttctct cttcagcgct tgtctagtaa gaaggaggca gcagcagcac tgtggggtgg 65760 tggaaagtgt accagctttg gagtcagacc attggatctc agccctacca ttttctactt 65820 agattttttt aggacaaatt tctccatctt tctaagcctc caattgctca cttacaaaat 65880 tgatataaca tttaccttgc aagattggta tggaaggtaa ttaacccagt atttagaaca 65940 tagtaattaa taaataacta ttattaccat cattactata gttaggacac tcactgttag 66000 gtgctataca aagaggatca taaaagggat gttgtcttgg gcttcttgga ataaatgttg 66060 tccttttact gtattttaga atatcattct gggtcataat tgtttgttgt cataataatg 66120 aaacatactt gaatattaaa ttaccctctt tttttatttt ttagccatgt tagaaggttc 66180 cccacagctg aatatggttg gcctctttcg acgaattatt tccaaagaag gaataccagg 66240 actttacaga ggcatcaccc caaacttcat gaaggtgctc cctgctgtag gcatcagtta 66300 tgtggtttat gaaaatatga agcaaacttt aggagtaacc cagaaatgat gttgcatttt 66360 ttgctttagc ctgataattg aaactttcaa caatctctgg agtgactttt tctcctcgaa 66420 ttgaaacaag tctatggcaa aagaagctgc atttttttca caaaagggaa gatggtaaca 66480 atggtcactt caaacttttg ggctaaatta tatgtacaca gaaatgttca aaatcatagt 66540 tttaatgtgt tttgaaaagg ccacacaatt atactttatc ttttcttaat aatcctgcaa 66600 atctctgccc tgaatccgaa atctgaaaat gtactggctt gaacaaaatt tgttttgtgt 66660 gttagagtta taaatcatta atctttattt cgggtggttt acgtttatgc cagttccttt 66720 atatttaaat ttcttgtttt atatattttg aatgtcttta tagatttctt taaatttcct 66780 tatagaacca ttaatagaaa atcattacat ttaaaatata ccttacagca aaagcatcca 66840 aataagtata gggtttatgt ccttattttt ctttcagctg aatacgaatg agcacagtgg 66900 tggaatttct gaagggaagt gatgaaatta tatttatttc agtgggcact tttccatttt 66960 accactgtac cattatttgg ttcctggagt tatacactaa ttttcagtat attactgtta 67020 aattaccaac acaaggcaat ttatttgaaa gattccgttt atcctgccat tgctttgaaa 67080 agcagcagga aacgaaatcc tttgacttgt atcagcttct gcagagcatc tttgttttcc 67140 tttgtccttt gtttcctacc ttttgaatca gattccgttt tagtcaggaa gacttcttgg 67200 gaccattctt agtaacctga aatttctttt ttaattgcat gaagtggatt gatcatgagc 67260 aaatgatgtg cttatttctc cctcactgtt gaatatcttt gaacttgctg ttttcaatat 67320 gggcagcaca aaggtgagag atacatatta atagtagtat gtattactct tatacattag 67380 atacctatat ttaaatgaaa ggcccaattt gtaaacatat acattcatat tctctcttgc 67440 cccaagtttt aggaacatgt taggatatag gagacttaat ttataataat gagagcattt 67500 ttttatttta ctaaagccat ttttatagtc aactatcttt tcttatttgt gtgattagaa 67560 cttagaaaaa tatttactag ttgaagttat tatcagtttt taatttagtt cttaaactca 67620 tttcacttct aataatttct gttataaatt gccagcattt taatgaaaat ctaatgatgt 67680 aataggcatt ttctttattt gaacctacct cttttatttt ctgaaccaaa gagaaagatg 67740 gactggtgtt tgtgaaacat ttttaaaaat gtagtttcat ttatattagt tatgtttgat 67800 aaatgtctca gtatttttat aatatgataa gcctgggatt ctacttttag ggttatttgt 67860 acttttgagt aatatataaa gtgacaatat taaggtacat gatcagctct ttctattttt 67920 actcgtaaaa attatggaaa tgaataattt tgctaacaac tttgaaattt caaacttctg 67980 gaaaatatga aaatattcat tgttcattat gaatttaaat tgtaaggtat gaatgtgatt 68040 tgtctgtaca tcttgtatct tttccaaaaa atgattctgt atcttttgga aaaaagccga 68100 gagttgaaga tagtatattt ctggtagtac tgaatattta cttacagttt ctatcaaaaa 68160 tatatatttg tttctaaaat tacttgtttt ccagttttta ttttttttag agaaaattct 68220 taagtctcag tttcctaatt gaaaaaaaaa aattataaat aaagcaaaaa ttgtatccta 68280 cagcttagct agcttagatg tttggcacca gtttgaatca tgctttttac agctggctcc 68340 atgtagtctt tccaaacatt ttggcctttc ctgagcagcc cttgtagata ttgtctgtat 68400 gatgcatttt gacacaaggt gatatttttt gtgatatcaa aattccacat ttacccatta 68460 gagttacagc cctggggttc acagtaccaa gggggaccca gagcctcagg attggccagg 68520 ctcattttgc cgtggagtat cagtttgtct tgaaattgtg ggaaaaaatt ctaagttgaa 68580 ttcactggta agtaattttt taaaatttca taatgcagat tacatccaaa atttgattta 68640 aaaattaaaa cataagactg cagagaaatt ctgcatttca actccaatac tatccagact 68700 tcagaaataa cttatcagtt atttctgtaa gcttcttgct tacctggata cctgacaggt 68760 gagatggctg tagcagacac tggcagttcc ctgcccacac acctgtccct gtccacagct 68820 gcacaaggca gctctgtgtg caattgccag catctgctcc tctgttctca gggaatcttt 68880 gttagaaaaa tgctgccata tttgtttctc acctattagt cttgtctccc agtcaagaga 68940 ataaatttat gcaagcagag attgtacttt acagtatttt gtctttgagc ttggcattag 69000 gttgcatttg taaaaatgtg gcatggcttc ctcatccccc aataggaact ttgccagccc 69060 ttttgttctc atggaacttc cttttttgaa aagagcacca aaggagtaaa aatactgtgg 69120 agggagcaac cctcctttgc catatgctct cattgggaga catgtggagc agtctgaagt 69180 catttaggcc actctctggg agagcacatc ctatgatgtt ctcccagcct agccccttcc 69240 actgtgctca agtccaagct gaccagcttt ctgaccacag tgtaaacaaa gatgattgtc 69300 agtgggcccc agaatcctat acccaga 69327 4 475 PRT Oryctolagus cuniculus 4 Met Leu Arg Trp Leu Arg Gly Phe Val Leu Pro Thr Ala Ala Cys Gln 1 5 10 15 Gly Ala Glu Pro Pro Thr Arg Tyr Glu Thr Leu Phe Gln Ala Leu Asp 20 25 30 Arg Asn Gly Asp Gly Val Val Asp Ile Arg Glu Leu Gln Glu Gly Leu 35 40 45 Lys Ser Leu Gly Ile Pro Leu Gly Gln Asp Ala Glu Glu Lys Ile Phe 50 55 60 Thr Thr Gly Asp Val Asn Lys Asp Gly Lys Leu Asp Phe Glu Glu Phe 65 70 75 80 Met Lys Tyr Leu Lys Asp His Glu Lys Lys Met Lys Leu Ala Phe Lys 85 90 95 Ser Leu Asp Lys Asn Asn Asp Gly Lys Ile Glu Ala Ser Glu Ile Val 100 105 110 Gln Ser Leu Gln Thr Leu Gly Leu Thr Ile Ser Glu Gln Gln Ala Glu 115 120 125 Leu Ile Leu Gln Ser Ile Asp Ala Asp Gly Thr Met Thr Val Asp Trp 130 135 140 Asn Glu Trp Arg Asp Tyr Phe Leu Phe Asn Pro Val Ala Asp Ile Glu 145 150 155 160 Glu Ile Ile Arg Phe Trp Lys His Ser Thr Gly Ile Asp Ile Gly Asp 165 170 175 Ser Leu Thr Ile Pro Asp Glu Phe Thr Glu Glu Glu Arg Lys Ser Gly 180 185 190 Gln Trp Trp Arg Gln Leu Leu Ala Gly Gly Ile Ala Gly Ala Val Ser 195 200 205 Arg Thr Ser Thr Ala Pro Leu Asp Arg Leu Lys Val Met Met Gln Val 210 215 220 His Gly Ser Lys Ser Met Asn Ile Phe Gly Gly Phe Arg Gln Met Ile 225 230 235 240 Lys Glu Gly Gly Val Arg Ser Leu Trp Arg Gly Asn Gly Thr Asn Val 245 250 255 Ile Lys Ile Ala Pro Glu Thr Ala Val Lys Phe Trp Val Tyr Glu Gln 260 265 270 Tyr Lys Lys Leu Leu Thr Glu Glu Gly Gln Lys Ile Gly Thr Phe Glu 275 280 285 Arg Phe Ile Ser Gly Ser Met Ala Gly Ala Thr Ala Gln Thr Phe Ile 290 295 300 Tyr Pro Met Glu Val Met Lys Thr Arg Leu Ala Val Gly Lys Thr Gly 305 310 315 320 Gln Tyr Ser Gly Ile Tyr Asp Cys Ala Lys Lys Ile Leu Lys Tyr Glu 325 330 335 Gly Phe Gly Ala Phe Tyr Lys Gly Tyr Val Pro Asn Leu Leu Gly Ile 340 345 350 Ile Pro Tyr Ala Gly Ile Asp Leu Ala Val Tyr Glu Leu Leu Lys Ser 355 360 365 His Trp Leu Asp Asn Phe Ala Lys Asp Ser Val Asn Pro Gly Val Leu 370 375 380 Val Leu Leu Gly Cys Gly Ala Leu Ser Ser Thr Cys Gly Gln Leu Ala 385 390 395 400 Ser Tyr Pro Leu Ala Leu Val Arg Thr Arg Met Gln Ala Gln Ala Met 405 410 415 Leu Glu Gly Ala Pro Gln Leu Asn Met Val Gly Leu Phe Arg Arg Ile 420 425 430 Ile Ser Lys Glu Gly Leu Pro Gly Leu Tyr Arg Gly Ile Thr Pro Asn 435 440 445 Phe Met Lys Val Leu Pro Ala Val Gly Ile Ser Tyr Val Val Tyr Glu 450 455 460 Asn Met Lys Gln Thr Leu Gly Val Thr Gln Lys 465 470 475 5 410 PRT Homo sapiens 5 Phe Val Leu Pro Thr Ala Ala Cys Gln Asp Ala Glu Gln Pro Thr Arg 1 5 10 15 Tyr Glu Thr Leu Phe Gln Ala Leu Asp Arg Asn Gly Asp Gly Val Val 20 25 30 Asp Ile Gly Glu Leu Gln Glu Gly Leu Arg Asn Leu Gly Ile Pro Leu 35 40 45 Gly Gln Asp Ala Glu Glu Lys Ile Phe Thr Thr Gly Asp Val Asn Lys 50 55 60 Asp Gly Lys Leu Asp Phe Glu Glu Phe Met Lys Tyr Leu Lys Asp His 65 70 75 80 Glu Lys Lys Met Lys Leu Ala Phe Lys Ser Leu Asp Lys Asn Asn Asp 85 90 95 Gly Lys Ile Glu Ala Ser Glu Ile Val Gln Ser Leu Gln Thr Leu Gly 100 105 110 Leu Thr Ile Ser Glu Gln Gln Ala Glu Leu Ile Leu Gln Ser Ile Asp 115 120 125 Val Asp Gly Thr Met Thr Val Asp Trp Asn Glu Trp Arg Asp Tyr Phe 130 135 140 Leu Phe Asn Pro Val Thr Asp Ile Glu Glu Ile Ile Arg Phe Trp Lys 145 150 155 160 His Ser Thr Gly Ile Asp Ile Gly Asp Ser Leu Thr Ile Pro Asp Glu 165 170 175 Phe Thr Glu Asp Glu Lys Lys Ser Gly Gln Trp Trp Arg Gln Leu Leu 180 185 190 Ala Gly Gly Ile Ala Gly Ala Val Ser Arg Thr Ser Thr Ala Pro Leu 195 200 205 Asp Arg Leu Lys Ile Met Met Gln Val His Gly Ser Lys Ser Asp Lys 210 215 220 Met Asn Ile Phe Gly Gly Phe Arg Gln Met Val Lys Glu Gly Gly Ile 225 230 235 240 Arg Ser Leu Trp Arg Gly Asn Gly Thr Asn Val Ile Lys Ile Ala Pro 245 250 255 Glu Thr Ala Val Lys Phe Trp Ala Tyr Glu Gln Tyr Lys Lys Leu Leu 260 265 270 Thr Glu Glu Gly Gln Lys Ile Gly Thr Phe Glu Arg Phe Ile Ser Gly 275 280 285 Ser Met Ala Gly Ala Thr Ala Gln Thr Phe Ile Tyr Pro Met Glu Val 290 295 300 Met Lys Thr Arg Leu Ala Val Gly Lys Thr Gly Gln Tyr Ser Gly Ile 305 310 315 320 Tyr Asp Cys Ala Lys Lys Ile Leu Lys His Glu Gly Leu Gly Ala Phe 325 330 335 Tyr Lys Gly Tyr Val Pro Asn Leu Leu Gly Ile Ile Pro Tyr Ala Gly 340 345 350 Ile Asp Leu Ala Val Tyr Glu Leu Leu Lys Ser Tyr Trp Leu Asp Asn 355 360 365 Phe Ala Lys Asp Ser Val Asn Pro Gly Val Met Val Leu Leu Gly Cys 370 375 380 Gly Ala Leu Ser Ser Thr Cys Gly Gln Leu Ala Ser Tyr Pro Leu Ala 385 390 395 400 Leu Val Arg Thr Arg Met Gln Ala Gln Ala 405 410 6 342 PRT Homo sapiens 6 Phe Gln Ala Leu Asp Arg Asn Gly Asp Gly Val Val Asp Ile Gly Glu 1 5 10 15 Leu Gln Glu Gly Leu Arg Asn Leu Gly Ile Pro Leu Gly Gln Asp Ala 20 25 30 Glu Glu Lys Ile Phe Thr Thr Gly Asp Val Asn Lys Asp Gly Lys Leu 35 40 45 Asp Phe Glu Glu Phe Met Lys Tyr Leu Lys Asp His Glu Lys Lys Met 50 55 60 Lys Leu Ala Phe Lys Ser Leu Asp Lys Asn Asn Asp Gly Lys Ile Glu 65 70 75 80 Ala Ser Glu Ile Val Gln Ser Leu Gln Thr Leu Gly Leu Thr Ile Ser 85 90 95 Glu Gln Gln Ala Glu Leu Ile Leu Gln Ser Ile Asp Val Asp Gly Thr 100 105 110 Met Thr Val Asp Trp Asn Glu Trp Arg Asp Tyr Phe Leu Phe Asn Pro 115 120 125 Val Thr Asp Ile Glu Glu Ile Ile Arg Phe Trp Lys His Ser Thr Gly 130 135 140 Ile Asp Ile Gly Asp Ser Leu Thr Ile Pro Asp Glu Phe Thr Glu Asp 145 150 155 160 Glu Lys Lys Ser Gly Gln Trp Trp Arg Gln Leu Leu Ala Gly Gly Ile 165 170 175 Ala Gly Ala Val Ser Arg Thr Ser Thr Ala Pro Leu Asp Arg Leu Lys 180 185 190 Ile Met Met Gln Val His Gly Ser Lys Ser Asp Lys Met Asn Ile Phe 195 200 205 Gly Gly Phe Arg Gln Met Val Lys Glu Gly Gly Ile Arg Ser Leu Trp 210 215 220 Arg Gly Asn Gly Thr Asn Val Ile Lys Ile Ala Pro Glu Thr Ala Val 225 230 235 240 Lys Phe Trp Ala Tyr Glu Gln Tyr Lys Lys Leu Leu Thr Glu Glu Gly 245 250 255 Gln Lys Ile Gly Thr Phe Glu Arg Phe Ile Ser Gly Ser Met Ala Gly 260 265 270 Ala Thr Ala Gln Thr Phe Ile Tyr Pro Met Glu Val Met Lys Thr Arg 275 280 285 Leu Ala Val Gly Lys Thr Gly Gln Tyr Ser Gly Ile Tyr Asp Cys Ala 290 295 300 Lys Lys Ile Leu Lys His Glu Gly Leu Gly Ala Phe Tyr Lys Gly Tyr 305 310 315 320 Val Pro Asn Leu Leu Gly Ile Ile Pro Tyr Ala Gly Ile Asp Leu Ala 325 330 335 Val Tyr Glu Leu Leu Lys 340 7 4 PRT Homo sapiens 7 Asn Gly Thr Asn 1 8 4 PRT Homo sapiens 8 Thr Arg Tyr Glu 1 9 4 PRT Homo sapiens 9 Thr Thr Gly Asp 1 10 4 PRT Homo sapiens 10 Thr Ile Ser Glu 1 11 4 PRT Homo sapiens 11 Thr Asp Ile Glu 1 12 4 PRT Homo sapiens 12 Thr Gly Ile Asp 1 13 4 PRT Homo sapiens 13 Thr Ile Pro Asp 1 14 4 PRT Homo sapiens 14 Thr Glu Asp Glu 1 15 4 PRT Homo sapiens 15 Ser Lys Ser Asp 1 16 6 PRT Homo sapiens 16 Gly Ile Pro Leu Gly Gln 1 5 17 6 PRT Homo sapiens 17 Gly Leu Thr Ile Ser Glu 1 5 18 6 PRT Homo sapiens 18 Gly Ile Asp Ile Gly Asp 1 5 19 6 PRT Homo sapiens 19 Gly Gly Ile Ala Gly Ala 1 5 20 6 PRT Homo sapiens 20 Gly Ile Ala Gly Ala Val 1 5 21 6 PRT Homo sapiens 21 Gly Gly Ile Arg Ser Leu 1 5 22 6 PRT Homo sapiens 22 Gly Asn Gly Thr Asn Val 1 5 23 6 PRT Homo sapiens 23 Gly Gln Lys Ile Gly Thr 1 5 24 6 PRT Homo sapiens 24 Gly Ser Met Ala Gly Ala 1 5 25 6 PRT Homo sapiens 25 Gly Gln Tyr Ser Gly Ile 1 5 26 6 PRT Homo sapiens 26 Gly Ile Tyr Asp Cys Ala 1 5 27 6 PRT Homo sapiens 27 Gly Ile Asp Leu Ala Val 1 5 28 6 PRT Homo sapiens 28 Gly Ala Leu Ser Ser Thr 1 5 29 6 PRT Homo sapiens 29 Gly Gln Leu Ala Ser Tyr 1 5 30 6 PRT Homo sapiens 30 Gly Leu Tyr Arg Gly Ile 1 5 31 6 PRT Homo sapiens 31 Gly Ile Thr Pro Asn Phe 1 5 32 13 PRT Homo sapiens 32 Asp Arg Asn Gly Asp Gly Val Val Asp Ile Gly Glu Leu 1 5 10 33 13 PRT Homo sapiens 33 Asp Val Asn Lys Asp Gly Lys Leu Asp Phe Glu Glu Phe 1 5 10 34 13 PRT Homo sapiens 34 Asp Lys Asn Asn Asp Gly Lys Ile Glu Ala Ser Glu Ile 1 5 10 35 601 DNA Homo sapiens 35 ttgcccacgc agatggctgt tgatcttttc tgcaacaaat ccaggagttt ctcctttttg 60 ttttataatt gctccaatag atgctttagg atttaactct ctgcttttta aagcagaatc 120 gccatcccag gtgtgcaacc acgaaaaaat tagacatccg tgagagacaa tgccctccat 180 ggcccagttt ccaggcagag agaagcagct ctgggctgac cgccaaggct ccggcccgag 240 agggtcttta agtggagtaa ccagtcttca agaccccgct cccaagccac cgacgcgctg 300 vcgctgcagc cctggacctg ctgggggcct cttcctcgga cccgcatgct gacagcggga 360 ctggcaactg ggcagaggtc gaccccgggt ccgcacagca cctcccgaga cccagctccc 420 agctccctca cttccggctc tctggaggcg ggcccggcca gtgccgccga ggccagcgcg 480 gcgagctcct ccccagcagc ggcgggacgg ccacaccctg cgcgccgcgc gggctcgggt 540 ggggtctccg ctcctgcgcc ctgcgcgccg cagccgcacc cccgacggcg ccccaaacgc 600 t 601 36 601 DNA Homo sapiens 36 agtttctcct ttttgtttta taattgctcc aatagatgct ttaggattta actctctgct 60 ttttaaagca gaatcgccat cccaggtgtg caaccacgaa aaaattagac atccgtgaga 120 gacaatgccc tccatggccc agtttccagg cagagagaag cagctctggg ctgaccgcca 180 aggctccggc ccgagagggt ctttaagtgg agtaaccagt cttcaagacc ccgctcccaa 240 gccaccgacg cgctgacgct gcagccctgg acctgctggg ggcctcttcc tcggacccgc 300 vtgctgacag cgggactggc aactgggcag aggtcgaccc cgggtccgca cagcacctcc 360 cgagacccag ctcccagctc cctcacttcc ggctctctgg aggcgggccc ggccagtgcc 420 gccgaggcca gcgcggcgag ctcctcccca gcagcggcgg gacggccaca ccctgcgcgc 480 cgcgcgggct cgggtggggt ctccgctcct gcgccctgcg cgccgcagcc gcacccccga 540 cggcgcccca aacgctgttg cgccgcgcgc cccgcccagc ccggcctcgc gctggtcccg 600 g 601 37 601 DNA Homo sapiens 37 tcgccatccc aggtgtgcaa ccacgaaaaa attagacatc cgtgagagac aatgccctcc 60 atggcccagt ttccaggcag agagaagcag ctctgggctg accgccaagg ctccggcccg 120 agagggtctt taagtggagt aaccagtctt caagaccccg ctcccaagcc accgacgcgc 180 tgacgctgca gccctggacc tgctgggggc ctcttcctcg gacccgcatg ctgacagcgg 240 gactggcaac tgggcagagg tcgaccccgg gtccgcacag cacctcccga gacccagctc 300 scagctccct cacttccggc tctctggagg cgggcccggc cagtgccgcc gaggccagcg 360 cggcgagctc ctccccagca gcggcgggac ggccacaccc tgcgcgccgc gcgggctcgg 420 gtggggtctc cgctcctgcg ccctgcgcgc cgcagccgca cccccgacgg cgccccaaac 480 gctgttgcgc cgcgcgcccc gcccagcccg gcctcgcgct ggtcccggtc tcgccccgca 540 gccctcgatc tcccgtgact tcctcggcca ggccgcctgc gcctctggga ccatgttgcg 600 c 601 38 601 DNA Homo sapiens 38 caaccacgaa aaaattagac atccgtgaga gacaatgccc tccatggccc agtttccagg 60 cagagagaag cagctctggg ctgaccgcca aggctccggc ccgagagggt ctttaagtgg 120 agtaaccagt cttcaagacc ccgctcccaa gccaccgacg cgctgacgct gcagccctgg 180 acctgctggg ggcctcttcc tcggacccgc atgctgacag cgggactggc aactgggcag 240 aggtcgaccc cgggtccgca cagcacctcc cgagacccag ctcccagctc cctcacttcc 300 kgctctctgg aggcgggccc ggccagtgcc gccgaggcca gcgcggcgag ctcctcccca 360 gcagcggcgg gacggccaca ccctgcgcgc cgcgcgggct cgggtggggt ctccgctcct 420 gcgccctgcg cgccgcagcc gcacccccga cggcgcccca aacgctgttg cgccgcgcgc 480 cccgcccagc ccggcctcgc gctggtcccg gtctcgcccc gcagccctcg atctcccgtg 540 acttcctcgg ccaggccgcc tgcgcctctg ggaccatgtt gcgctggctg cgggacttcg 600 t 601 39 601 DNA Homo sapiens 39 caaggctccg gcccgagagg gtctttaagt ggagtaacca gtcttcaaga ccccgctccc 60 aagccaccga cgcgctgacg ctgcagccct ggacctgctg ggggcctctt cctcggaccc 120 gcatgctgac agcgggactg gcaactgggc agaggtcgac cccgggtccg cacagcacct 180 cccgagaccc agctcccagc tccctcactt ccggctctct ggaggcgggc ccggccagtg 240 ccgccgaggc cagcgcggcg agctcctccc cagcagcggc gggacggcca caccctgcgc 300 kccgcgcggg ctcgggtggg gtctccgctc ctgcgccctg cgcgccgcag ccgcaccccc 360 gacggcgccc caaacgctgt tgcgccgcgc gccccgccca gcccggcctc gcgctggtcc 420 cggtctcgcc ccgcagccct cgatctcccg tgacttcctc ggccaggccg cctgcgcctc 480 tgggaccatg ttgcgctggc tgcgggactt cgtgctgccc accgcggcct gccaggacgc 540 ggagcagccg acgcgctacg agaccctctt ccaggcactg gaccgcaatg gggacggagt 600 g 601 40 601 DNA Homo sapiens 40 gccaccgacg cgctgacgct gcagccctgg acctgctggg ggcctcttcc tcggacccgc 60 atgctgacag cgggactggc aactgggcag aggtcgaccc cgggtccgca cagcacctcc 120 cgagacccag ctcccagctc cctcacttcc ggctctctgg aggcgggccc ggccagtgcc 180 gccgaggcca gcgcggcgag ctcctcccca gcagcggcgg gacggccaca ccctgcgcgc 240 cgcgcgggct cgggtggggt ctccgctcct gcgccctgcg cgccgcagcc gcacccccga 300 mggcgcccca aacgctgttg cgccgcgcgc cccgcccagc ccggcctcgc gctggtcccg 360 gtctcgcccc gcagccctcg atctcccgtg acttcctcgg ccaggccgcc tgcgcctctg 420 ggaccatgtt gcgctggctg cgggacttcg tgctgcccac cgcggcctgc caggacgcgg 480 agcagccgac gcgctacgag accctcttcc aggcactgga ccgcaatggg gacggagtgg 540 tggacatcgg cgagctgcag gaggggctca ggaacctggg catccctctg ggccaggacg 600 c 601 41 601 DNA Homo sapiens 41 tggggccgcg accggcgacc ccggtaacag aagtgggtca taatacgaaa gtctactggt 60 atttgtccag ataaaatgag tgttgtggac actctggccc acgggcactg ttaaattttt 120 aagacacttt tgtcctgaat ccatcccagg ttctttgttt tctgttttaa taccttgcag 180 acatgtaatc cgttttagct gtcagacttc agtgggtccc aagttttgta taaaggcgca 240 cacattcgat ctctttcgaa gctgctttgt tacagcagct atgtgtattg tctactgttt 300 saaaactgtt tgaaaaccaa tcgcgtgttt cccccacttc ctgttgagaa ggaatggcgg 360 cattccattg tttaagacat tcctaggtta atgccctagg tacataaatt gatctgaagg 420 gttgacttga cctgcgactg agcaatttca ttttctctga gtcatcttaa ctgtgcccct 480 gaacttctgc ccctttagta gggtggagat atgtggaact tctccaaccc tgttgaagcg 540 ttccctgaca ctggcattct cttatccaaa gagggaaagt gattaggtta ctatgagggc 600 c 601 42 601 DNA Homo sapiens 42 gctgattgtc ccagaaatgg cccagttgga gttccccacc atgtccaatc attggctgga 60 agcagcccag gaaagggacg accttgctgc agtgcatcag cagatgccag ggttagaggc 120 tagagagtgg aagtcaactg tgttcctcac agtaggtgcc tttgaaggga gatctcagtg 180 gtacaactcc atggtcccta caatatacaa aagctctttg gagtgctcaa tgatttttaa 240 gattgtaaag ggatcctgag atcaaaaagc ttgagaattg ctgctgtatc accattttta 300 ygtaactgca tcatattctg ttatatgttt gtgtcatagt atatgttacc aattcttttt 360 aaatcacctt ttactttatt gatagtttaa aaacgattgt aagtgaaatt gcaatggatg 420 tcctttgtat tcattttctc attctggtcc agttactttc gtaggataaa ttttgaggag 480 tggacattgc tgagtctgaa ggtaacacac attttaaact gggatacgta ttgcctttcg 540 gaaaccttag acccattttc actcttttga ctgacagtgc ttgcttctcc acatcctcgc 600 t 601 43 601 DNA Homo sapiens 43 gaagggagat ctcagtggta caactccatg gtccctacaa tatacaaaag ctctttggag 60 tgctcaatga tttttaagat tgtaaaggga tcctgagatc aaaaagcttg agaattgctg 120 ctgtatcacc atttttacgt aactgcatca tattctgtta tatgtttgtg tcatagtata 180 tgttaccaat tctttttaaa tcacctttta ctttattgat agtttaaaaa cgattgtaag 240 tgaaattgca atggatgtcc tttgtattca ttttctcatt ctggtccagt tactttcgta 300 rgataaattt tgaggagtgg acattgctga gtctgaaggt aacacacatt ttaaactggg 360 atacgtattg cctttcggaa accttagacc cattttcact cttttgactg acagtgcttg 420 cttctccaca tcctcgctca ttcagggtat cagtctttgt aaagtctcct attctgcagg 480 tgaaattcct tttcatttcc tgtcttagtc catttagtgt tgctatagtg gaatatctga 540 gacagggtaa tttataaaga aaagacattt atttagctca cagttccgca ggctgggaag 600 t 601 44 601 DNA Homo sapiens 44 cagttacttt cgtaggataa attttgagga gtggacattg ctgagtctga aggtaacaca 60 cattttaaac tgggatacgt attgcctttc ggaaacctta gacccatttt cactcttttg 120 actgacagtg cttgcttctc cacatcctcg ctcattcagg gtatcagtct ttgtaaagtc 180 tcctattctg caggtgaaat tccttttcat ttcctgtctt agtccattta gtgttgctat 240 agtggaatat ctgagacagg gtaatttata aagaaaagac atttatttag ctcacagttc 300 ygcaggctgg gaagtttaag aagcgtggtg ctggcatctg ctggactcct ggggagggct 360 ttcctgctgt gtcacaacat ggtggaaagt caaagtggaa gtggacatgt gtgaagaagc 420 aaaatccgag gggtgtcctg gctttatagc aacccagcct cgagggaact gatccattac 480 tgagggaact aattcagtct catgagagag agaactcact cactactgca agaatgacac 540 caagccattc atgagggatc tgcctccgta accctgacac ctcctgctag gtccctcctc 600 c 601 45 601 DNA Homo sapiens 45 catttagtgt tgctatagtg gaatatctga gacagggtaa tttataaaga aaagacattt 60 atttagctca cagttccgca ggctgggaag tttaagaagc gtggtgctgg catctgctgg 120 actcctgggg agggctttcc tgctgtgtca caacatggtg gaaagtcaaa gtggaagtgg 180 acatgtgtga agaagcaaaa tccgaggggt gtcctggctt tatagcaacc cagcctcgag 240 ggaactgatc cattactgag ggaactaatt cagtctcatg agagagagaa ctcactcact 300 rctgcaagaa tgacaccaag ccattcatga gggatctgcc tccgtaaccc tgacacctcc 360 tgctaggtcc ctcctcccaa cacggccaca tcagggatca gacttcaaca tgagtttttg 420 tggggacaaa caaaacgtag cacttgcttt gccttttggt tctattcaca tcctccacag 480 gattgcatta tgcctaccca tttggtgagg gcagtcttct ttaattggtt tactgattca 540 aatgctaccc tcctccagag acatcctcac agacacaccc agaaatcatg ttttaccagt 600 t 601 46 601 DNA Homo sapiens 46 ttcctgctgt gtcacaacat ggtggaaagt caaagtggaa gtggacatgt gtgaagaagc 60 aaaatccgag gggtgtcctg gctttatagc aacccagcct cgagggaact gatccattac 120 tgagggaact aattcagtct catgagagag agaactcact cactactgca agaatgacac 180 caagccattc atgagggatc tgcctccgta accctgacac ctcctgctag gtccctcctc 240 ccaacacggc cacatcaggg atcagacttc aacatgagtt tttgtgggga caaacaaaac 300 rtagcacttg ctttgccttt tggttctatt cacatcctcc acaggattgc attatgccta 360 cccatttggt gagggcagtc ttctttaatt ggtttactga ttcaaatgct accctcctcc 420 agagacatcc tcacagacac acccagaaat catgttttac cagttatctg ggcatccctt 480 agtccagacg agttgataca taaaattaac catcacacat gggatagaat taggattaca 540 cagtcaacct ttatgggaga aaatttcaga ggcatgtcag gggtttatgt aatgtcaagg 600 a 601 47 601 DNA Homo sapiens 47 tgtttattgc attgagtgga atcaggattt cactccatta agtaattcct ctgttaacaa 60 agagggttca tttcattttt atttcattaa tattgctttt tttttttttt ttctggagac 120 agaatcttgc tctatcacca aggctggagt gcagtggtgc gatctcggct cactgcagcc 180 tctgcttcct ggattcaagc gattcttgtg cctcagcctc ccaagcagct gagattacag 240 gcacatgcca ccacacctgg ttaacttttg tattttctag tagagatggg attttgccat 300 kttggtcagg ctggtcttga attcctggcc tctagtgatc tgcctgcctc tgcctctgaa 360 agtgctaaga ttacaggcat gagctaccat ggccagccca tttccttaat attttaattg 420 tcagacatgt tatggtttct ggcacaatat taagaagaca tgatatgaaa tcacagggtg 480 aattttaggg catcacaaca gaaagattat ggtataagaa aaacaatgga attccaacta 540 catttctgtc aaatgttcta aaatatataa aatctgtatc ttttgtgttc tctcctgatt 600 t 601 48 601 DNA Homo sapiens 48 ttatttcatt aatattgctt tttttttttt ttttctggag acagaatctt gctctatcac 60 caaggctgga gtgcagtggt gcgatctcgg ctcactgcag cctctgcttc ctggattcaa 120 gcgattcttg tgcctcagcc tcccaagcag ctgagattac aggcacatgc caccacacct 180 ggttaacttt tgtattttct agtagagatg ggattttgcc atgttggtca ggctggtctt 240 gaattcctgg cctctagtga tctgcctgcc tctgcctctg aaagtgctaa gattacaggc 300 dtgagctacc atggccagcc catttcctta atattttaat tgtcagacat gttatggttt 360 ctggcacaat attaagaaga catgatatga aatcacaggg tgaattttag ggcatcacaa 420 cagaaagatt atggtataag aaaaacaatg gaattccaac tacatttctg tcaaatgttc 480 taaaatatat aaaatctgta tcttttgtgt tctctcctga tttatattct aaatttgatg 540 ttatccttct ctgcagaaat aaagtgtctg aaagaatgaa aaaaatggaa gaattcttta 600 g 601 49 601 DNA Homo sapiens 49 atgaaatcac agggtgaatt ttagggcatc acaacagaaa gattatggta taagaaaaac 60 aatggaattc caactacatt tctgtcaaat gttctaaaat atataaaatc tgtatctttt 120 gtgttctctc ctgatttata ttctaaattt gatgttatcc ttctctgcag aaataaagtg 180 tctgaaagaa tgaaaaaaat ggaagaattc tttagtaagg tataaaatac cctttctatc 240 tttgtagcat tctaagcctt ttgtcacctt tccaaactcc caacatgcca tattccctga 300 staggccaca gccatgtaca ttgatccctt tattttcttc tctctgcctg agatttctct 360 cattccccct tctctgcctg gtatatgatt gcccattgtt taaggcccca actcaccttt 420 ataatcttcc tagcccactt tctttatcgg tattccagaa aaaacaaaag aagcttccac 480 aagacaacat tctgtaatac actgcttaac ttcttttgac cctgctgagt tcaaaaatct 540 tatcttttta aggattgaat ggagtccacc aaggtatcta tatttgacag gatttatgaa 600 a 601 50 601 DNA Homo sapiens 50 gattgcccat tgtttaaggc cccaactcac ctttataatc ttcctagccc actttcttta 60 tcggtattcc agaaaaaaca aaagaagctt ccacaagaca acattctgta atacactgct 120 taacttcttt tgaccctgct gagttcaaaa atcttatctt tttaaggatt gaatggagtc 180 caccaaggta tctatatttg acaggattta tgaaaacaaa aggatttgtt gagaaagttt 240 gaagcctaac tctgaaacgt ggatcatagt gtttactaca cattaactgt tttagtggat 300 rtaatagtta ttattatagg ctgtggaatc agaacagggt tcaaatgttt tcaccgcttg 360 ctagactgtg gccttgggca tgttatttaa tgcctggagg cctcaaatgt taactaggaa 420 tggtaagacc tacccagtaa cttagcataa atagtaaatt cattcattta atgttttcaa 480 acagtgccag acattgttta atgaactggg gatatagtgg tgaacaacac tgacagcgtt 540 cttcattgta ttctcaaaac cctccctata gtaagtaggt ctgtgtgtgt gtgtaggtgc 600 a 601 51 601 DNA Homo sapiens 51 taatcttcct agcccacttt ctttatcggt attccagaaa aaacaaaaga agcttccaca 60 agacaacatt ctgtaataca ctgcttaact tcttttgacc ctgctgagtt caaaaatctt 120 atctttttaa ggattgaatg gagtccacca aggtatctat atttgacagg atttatgaaa 180 acaaaaggat ttgttgagaa agtttgaagc ctaactctga aacgtggatc atagtgttta 240 ctacacatta actgttttag tggatgtaat agttattatt ataggctgtg gaatcagaac 300 rgggttcaaa tgttttcacc gcttgctaga ctgtggcctt gggcatgtta tttaatgcct 360 ggaggcctca aatgttaact aggaatggta agacctaccc agtaacttag cataaatagt 420 aaattcattc atttaatgtt ttcaaacagt gccagacatt gtttaatgaa ctggggatat 480 agtggtgaac aacactgaca gcgttcttca ttgtattctc aaaaccctcc ctatagtaag 540 taggtctgtg tgtgtgtgta ggtgcatggg gaataaaaaa taataagcaa ataatgaaca 600 g 601 52 601 DNA Homo sapiens 52 ttaaggattg aatggagtcc accaaggtat ctatatttga caggatttat gaaaacaaaa 60 ggatttgttg agaaagtttg aagcctaact ctgaaacgtg gatcatagtg tttactacac 120 attaactgtt ttagtggatg taatagttat tattataggc tgtggaatca gaacagggtt 180 caaatgtttt caccgcttgc tagactgtgg ccttgggcat gttatttaat gcctggaggc 240 ctcaaatgtt aactaggaat ggtaagacct acccagtaac ttagcataaa tagtaaattc 300 rttcatttaa tgttttcaaa cagtgccaga cattgtttaa tgaactgggg atatagtggt 360 gaacaacact gacagcgttc ttcattgtat tctcaaaacc ctccctatag taagtaggtc 420 tgtgtgtgtg tgtaggtgca tggggaataa aaaataataa gcaaataatg aacagggtaa 480 tttcaaaaag cagaaagagc tattcaacaa aactacctgc cttttattag atgaaactct 540 caactctatg gtttgttctc tcctgtcaat tctgttaaat gctgtcagcc tgttttcctt 600 a 601 53 601 DNA Homo sapiens 53 aactgtttta gtggatgtaa tagttattat tataggctgt ggaatcagaa cagggttcaa 60 atgttttcac cgcttgctag actgtggcct tgggcatgtt atttaatgcc tggaggcctc 120 aaatgttaac taggaatggt aagacctacc cagtaactta gcataaatag taaattcatt 180 catttaatgt tttcaaacag tgccagacat tgtttaatga actggggata tagtggtgaa 240 caacactgac agcgttcttc attgtattct caaaaccctc cctatagtaa gtaggtctgt 300 stgtgtgtgt aggtgcatgg ggaataaaaa ataataagca aataatgaac agggtaattt 360 caaaaagcag aaagagctat tcaacaaaac tacctgcctt ttattagatg aaactctcaa 420 ctctatggtt tgttctctcc tgtcaattct gttaaatgct gtcagcctgt tttccttatc 480 accctggcca cgacttctgt cttttctgct tggtcctgta gactctaacc caaggctcat 540 tctctgcctg gctatctgcc ttctgtggct ctttgccact acctacattt tctgtgttgc 600 a 601 54 601 DNA Homo sapiens 54 ctggggatat agtggtgaac aacactgaca gcgttcttca ttgtattctc aaaaccctcc 60 ctatagtaag taggtctgtg tgtgtgtgta ggtgcatggg gaataaaaaa taataagcaa 120 ataatgaaca gggtaatttc aaaaagcaga aagagctatt caacaaaact acctgccttt 180 tattagatga aactctcaac tctatggttt gttctctcct gtcaattctg ttaaatgctg 240 tcagcctgtt ttccttatca ccctggccac gacttctgtc ttttctgctt ggtcctgtag 300 mctctaaccc aaggctcatt ctctgcctgg ctatctgcct tctgtggctc tttgccacta 360 cctacatttt ctgtgttgca cagggaagga ccattccctg tggaccataa aattctcttt 420 ttgaaagaat tcattcttga ttgggccaca gcacatcttg tgaaacagca ttagacattt 480 gccactgctc agcagctctg ggggaaaatg tttactgaga agcgtacagt agtttttttg 540 actaaccatg gtgcaacctc ctcccagagg gaaacctatg agtatttcaa ggacatgtga 600 t 601 55 601 DNA Homo sapiens 55 ttaaacgaat tattgtagaa acagaaaaac aaatactgtg ttctcattta cagggggagc 60 taaaccttgg gtaaatgggg cataaagatg ggaacaatag acactaggga ctccaaaagg 120 ggggagggag ggaggagggc aagggctgga aagcttccta ctgggtactt tgttcacaac 180 ctgggtgatg gcacgattag gagctcaaac cccagtatca cacagtatac ccttgtaaca 240 agctgatggt gtaacccctg aatctacaat aaaattattt tattttaaaa aatcattata 300 rggattttta aaaagaagga ttcctagaca ggtgcagcca aacaattttt tttaaatgtt 360 ggcaggccgc caccgccagt cacttatgct gcaatagccc atgtcccaac attcccaacc 420 tacttctctc caaaagagaa gctatacttt cagatggccc tgtgctgggt tctccctgga 480 agtttctggg gaaaggggct tgagttgccc cgactggact cttcctggag tgggagccgg 540 ggcttctgat cagacgtgag tgaggcagga actccgcggt ctcccagcgc agcccagagt 600 g 601 56 601 DNA Homo sapiens 56 catgtcccaa cattcccaac ctacttctct ccaaaagaga agctatactt tcagatggcc 60 ctgtgctggg ttctccctgg aagtttctgg ggaaaggggc ttgagttgcc ccgactggac 120 tcttcctgga gtgggagccg gggcttctga tcagacgtga gtgaggcagg aactccgcgg 180 tctcccagcg cagcccagag tgcggtccca cgcaggtccc gggtcctgcg cgctcgcgcc 240 tttgcgctga agccgttagg atgagccctc tccttccaga gctttaaccg atgaaggtgc 300 wttgtgtttg gcgcccctga ggaggatgct gtcttaggcc tcttcccact ggacgtgtgt 360 ggtgggcaga gatcccgttc gtcggtcgca cttccacccc gctggggctc actcaggccg 420 cggagctgcg agggagacat cctcgatgga ctccctctac ggagatctct tttggtacct 480 ggactataac aaggatggga ccttggacat ttttgagctt caggaaggcc tggaggatgt 540 aggggccatt caatctctag aggaagcgaa ggtgggtctc actggggctg taatcagaga 600 g 601 57 601 DNA Homo sapiens 57 accccgctgg ggctcactca ggccgcggag ctgcgaggga gacatcctcg atggactccc 60 tctacggaga tctcttttgg tacctggact ataacaagga tgggaccttg gacatttttg 120 agcttcagga aggcctggag gatgtagggg ccattcaatc tctagaggaa gcgaaggtgg 180 gtctcactgg ggctgtaatc agagagacgt tggggctggg agccctggag aggcattggg 240 cagagagggc aaaatttaca tgttgtcaag cttgacctgg gcccactgca gtgttcaggt 300 sgttgaccag cgttaccgtt tattaagaat aacaacacag ctaacacatt tctcaagtat 360 ttttctccgt tttctccttg gctgtagtaa aatctccaac ttcagattgc tctcaagatg 420 ttggctacat acagccttgt cttaggagtc accttgttca atgtgctcac ctgtcattag 480 tcacccagag gggcgtctag gctaaagatg cgccctcccc agttcagaga actggaataa 540 tcactctacg tgtatttggg agtggggtgg tgattggaaa ttttctgatg ttatgttttg 600 g 601 58 601 DNA Homo sapiens 58 gtggttgacc agcgttaccg tttattaaga ataacaacac agctaacaca tttctcaagt 60 atttttctcc gttttctcct tggctgtagt aaaatctcca acttcagatt gctctcaaga 120 tgttggctac atacagcctt gtcttaggag tcaccttgtt caatgtgctc acctgtcatt 180 agtcacccag aggggcgtct aggctaaaga tgcgccctcc ccagttcaga gaactggaat 240 aatcactcta cgtgtatttg ggagtggggt ggtgattgga aattttctga tgttatgttt 300 yggtttctgt tcctggaagg gggcagtgga agtggctttt actctcgggt ttcactagtg 360 ctgaggtttc ctcataatat gccttaattg atagacccta gttatcagta ccgagcttag 420 gctaaccctt ctcttcccca gaaggctaac ctacaggctc cttctcagca tgttgtgctt 480 cgtacatact cctattgcag tatttccaag tcatttttca tttggaattt attattgtat 540 ataataatta ctttataagt atatttgctc tttggatgtt tgacccggta gactgggaga 600 t 601 59 601 DNA Homo sapiens 59 gtcatgttat ttaatgcctg gaggcctcaa atgttaacta ggtaatggta agacctaccc 60 agtaacttag cataaatagt aaattcattc atttaatgtt ttcaaacagt gccagacatt 120 gtttaatgaa ctggggatat agtggtgaac aacactgaca gcgttcttca ttgtattctc 180 aaaaccctcc ctatagtaag taggtctgtg tgtgtgtgta ggtgcatggg gaataaaaaa 240 taataagcaa ataatgaaca ataaaattat tttatttaaa aaaaaagaaa tgatacttac 300 vttgtcgtgt taagatacaa aagcaataac tttttattgt gaaaatagtc tgtttttgaa 360 caatatattg ttttgttttt tcctgtgaaa gttgagaaac taaatatacg aagagataat 420 ggtcagacca taaataaaaa tagaactttg actcaaaatt tacagcagtc tgcccagaaa 480 accagccctt tatctaaaat aaacagacca ggaaaccagc ctgttatgtc agacttatag 540 gaagtcaggt tgctatctct agagacaata cacaaagcta tgcaataact gctgtaacag 600 c 601 60 601 DNA Homo sapiens 60 tacaggcgtg agccaccatg cgcccagcca tagactatat atttttgatc tgataactgg 60 ttcagctact aagtgactaa caggcaagta gcatctatag tgtggatatg ctggacaaaa 120 ggacattcac ctcctgggca ggatggcaca gaatgttgag agattttatc atgctactca 180 gaatggtgtg caatttaaaa cttatgagtt gtttgtttct ggagttttcc atttaatagt 240 tcagaccatg gattgaccgc aggtaactga aactgtggag agtgaaactg tggataaggg 300 rggactattg tattgttaag tcagactcat taggcaatca taactcttga tttgccatca 360 gaaatgctgc agaaatatgg gttaaaaaaa actgttcaaa aatagggtca gggatgtcct 420 ttaacttgtt acttccaaaa tgttagtgaa aactgtggcc ccaaagagtg aaaggaacaa 480 atgactaaga gaaaatcttg ttttcaggat gacagattaa aaaagaagca acttgctgaa 540 acactgaaaa tctctccact tgtaagataa cacaaaactg gctaaaactg gttggaatga 600 a 601 61 601 DNA Homo sapiens 61 atagggtcag ggatgtcctt taacttgtta cttccaaaat gttagtgaaa actgtggccc 60 caaagagtga aaggaacaaa tgactaagag aaaatcttgt tttcaggatg acagattaaa 120 aaagaagcaa cttgctgaaa cactgaaaat ctctccactt gtaagataac acaaaactgg 180 ctaaaactgg ttggaatgaa tatggccaac tcaagtctgc acagaactaa cttggtgatg 240 ttacagccca aatttccacc acatatttta tactaactcc ccccggattt tcacacatga 300 yctgtgaggt agcatgaaga ggtaactatg catgcctaag gacttgggag acctccccat 360 ttccttccac caatcaccca ctaatcccag aatccgcccc caaacctttt ctaataacta 420 ccttaaagcc agcataggga gacagatttg agctggactc ctgtcttctt gtgggtcacc 480 ttgcaataaa aagcttttct tttctcaaca cctggtatta tagtattgac ttctagttca 540 tcgggcagca agcccctttt ggtcggtgac tattcttgtt cgctgatatt tccattggcc 600 a 601 62 601 DNA Homo sapiens 62 actaatccca gaatccgccc ccaaaccttt tctaataact accttaaagc cagcataggg 60 agacagattt gagctggact cctgtcttct tgtgggtcac cttgcaataa aaagcttttc 120 ttttctcaac acctggtatt atagtattga cttctagttc atcgggcagc aagccccttt 180 tggtcggtga ctattcttgt tcgctgatat ttccattggc caaaatataa acctcttaga 240 tgaaacttca gtacgtaaat ggcgccacag aatgctgtga catttttctc ttggattata 300 rcaggttact ttactgaata ccgtaggcag ttataacaca ctaagtattt gtgtatctaa 360 acatagaaaa gatacagtaa aaatatggta atttttttca acttttagtt gagatttgga 420 gggtatgtgc acatttgtta caagggtata ttgcatgatg ctgaggtttg gggtacaatt 480 gaaccctgtc acccaggtag tgagcatagt acccaatcga taatttttca acccttgtcc 540 attccctccc cgttcttgta gtccccagtt tctgcttttc ccatctttat atccgtgtgc 600 a 601 63 601 DNA Homo sapiens 63 ctcaacacct ggtattatag tattgacttc tagttcatcg ggcagcaagc cccttttggt 60 cggtgactat tcttgttcgc tgatatttcc attggccaaa atataaacct cttagatgaa 120 acttcagtac gtaaatggcg ccacagaatg ctgtgacatt tttctcttgg attatagcag 180 gttactttac tgaataccgt aggcagttat aacacactaa gtatttgtgt atctaaacat 240 agaaaagata cagtaaaaat atggtaattt ttttcaactt ttagttgaga tttggagggt 300 rtgtgcacat ttgttacaag ggtatattgc atgatgctga ggtttggggt acaattgaac 360 cctgtcaccc aggtagtgag catagtaccc aatcgataat ttttcaaccc ttgtccattc 420 cctccccgtt cttgtagtcc ccagtttctg cttttcccat ctttatatcc gtgtgcaccc 480 catgttttgc tcccatgtgt atgtgagaac ttgtggtgtt tggttttcta tttctgcgtt 540 gattcgctta ggataatggc cttcagctgc atccatgttg ctgcagagga cgtgatttta 600 t 601 64 601 DNA Homo sapiens 64 aggagtttat caattttatt agtcttttca aagaaccatc ttttggcttt gttaatcctc 60 ccaatggtgt gttttctttc tcattacttt ttgctcttta tttccttcaa cttctttttt 120 gcttaatttt aaaataattt cttgagattg agataagcct caatgatggg tcaccgattt 180 ccagtctttc ttcttttcta attatgcatt ttaaaccaga aatctttctc taagtgtagc 240 tttagttgca gctcacaagt ttcagatctg tctctcagtc tggaggttgg agatctgacc 300 rtgaccatga aaccatccag tcacaatgtg gcattatttt tttaattttt tttttttttt 360 ttgagataga gtttcactct tattgcctag gctggtgtgc aatggtgcga tctcggctca 420 cagcaacctc cacctcccag gttcaagcga ttcttttgcc tcagcctccc aagtagctgg 480 gattacaggc atgcgccacc atgcccaact aattttgtat ttttagtaga gatgggggtt 540 ctccatgttg gtcaggttgg tcttgaactc ccgacctcag gtgatccgcc cacctcagcc 600 t 601 65 601 DNA Homo sapiens 65 gtggcattat tggttcatat ttttattttt tagacttcct taatgcaaaa catatacagt 60 tgatcctcat tatttgggga ttctgtattt gcaaatttgc ctactcaata aaatttatcc 120 ccaaagtaac cccaaaatat atactcacag tactttccca ggcattcatg gacatgcaca 180 gagcagtgaa aaacttgagt tgctcagcat gtacattcct agctagtaga ataaggcaat 240 actctgcctt cttgtttcag ctctcatact attaactagc aagtatccct ttcaaggtct 300 rttttgtgcc agtttttgca tttttgtatt tttgttggta atttcctttt taaaatgttc 360 cccaaaggta gtgctgaagt gctgtctagt gttcctaagt gcaagaaagc catagcatgc 420 cttatggaga aaatatatgc gttggataag ctttgcccca aattcaatgt tagtgaatca 480 acagcacaca ttaaatgagg tgccttcaaa cagaaacaga cataagacat ggttatgtat 540 taatcagttg atgaaagtgt tgtaatcaga ggctcacagg aacctaaccc tgtttttcct 600 g 601 66 601 DNA Homo sapiens 66 ctcacagtac tttcccaggc attcatggac atgcacagag cagtgaaaaa cttgagttgc 60 tcagcatgta cattcctagc tagtagaata aggcaatact ctgccttctt gtttcagctc 120 tcatactatt aactagcaag tatccctttc aaggtctatt ttgtgccagt ttttgcattt 180 ttgtattttt gttggtaatt tcctttttaa aatgttcccc aaaggtagtg ctgaagtgct 240 gtctagtgtt cctaagtgca agaaagccat agcatgcctt atggagaaaa tatatgcgtt 300 kgataagctt tgccccaaat tcaatgttag tgaatcaaca gcacacatta aatgaggtgc 360 cttcaaacag aaacagacat aagacatggt tatgtattaa tcagttgatg aaagtgttgt 420 aatcagaggc tcacaggaac ctaaccctgt ttttcctgta ggaacaatgg tttggtattt 480 gctaattcag tgtttgcaat gaatatagaa ctttatggaa gatgattgct gtgaataatg 540 agaattaacc atatctcttt aagagtgcat ttctaaagga gaatattcag aagggtattt 600 g 601 67 601 DNA Homo sapiens 67 tcagcatgta cattcctagc tagtagaata aggcaatact ctgccttctt gtttcagctc 60 tcatactatt aactagcaag tatccctttc aaggtctatt ttgtgccagt ttttgcattt 120 ttgtattttt gttggtaatt tcctttttaa aatgttcccc aaaggtagtg ctgaagtgct 180 gtctagtgtt cctaagtgca agaaagccat agcatgcctt atggagaaaa tatatgcgtt 240 ggataagctt tgccccaaat tcaatgttag tgaatcaaca gcacacatta aatgaggtgc 300 sttcaaacag aaacagacat aagacatggt tatgtattaa tcagttgatg aaagtgttgt 360 aatcagaggc tcacaggaac ctaaccctgt ttttcctgta ggaacaatgg tttggtattt 420 gctaattcag tgtttgcaat gaatatagaa ctttatggaa gatgattgct gtgaataatg 480 agaattaacc atatctcttt aagagtgcat ttctaaagga gaatattcag aagggtattt 540 gcataatttc tttactaaca gatgctgcct ctcactgtcc ttacatggtc cagattctca 600 t 601 68 601 DNA Homo sapiens 68 tctctcagaa tcctgtcatc tcctccaggg tcctttctcc aagaaagtct atcctttcac 60 cactaacagt aattttggtc ttcctctttt tctggagaag tcagctgttt atgctgcttc 120 agcaccagac cctctcttac tttgttttgt ttcattcttt ttcatgtaca gtagtcttag 180 gattctcatg agcctgtgag ctgctagaag gaaatacagc agtgcttaca tttattgctt 240 ctattttatt ttctattttc tcttcctgtc ttctgattgt tctccttctg tccacaaaca 300 ygctctaatt tccctagtat taaaaatttt ctgtcttttg ttgttctttt atccttgctc 360 ccttattttt actgccagat ttttattttt atttatttat ttttgagatg gagtctcact 420 ctgtcaccca ggctggggtg cagtggcgcg atctcagctc actgcaacct ccgcctccca 480 gcttcaagca attttcctct tttagcctcc caagtagctg ggattatggg cacctgccac 540 catgcctggc tgatttttct atttttagta gagacggggt ttcaccatgt tggccacact 600 g 601 69 601 DNA Homo sapiens variation (301)...(301) T may be either present or absent 69 cactctgtca cccaggctgg ggtgcagtgg cgcgatctca gctcactgca acctccgcct 60 cccagcttca agcaattttc ctcttttagc ctcccaagta gctgggatta tgggcacctg 120 ccaccatgcc tggctgattt ttctattttt agtagagacg gggtttcacc atgttggcca 180 cactgctctc taactgctga cctcaggtga accacccgcc tcagcctcca aaagtgctgg 240 gattgcaggt gtgagtcact gtgcctggcc ttttactgcc agatttttaa aagaatagtc 300 tgtgctttag ctctatttcc tcatttacta cttctcttta actcagtcat atatgatgtt 360 ttgcatagta aatgtctagt aatttattaa aaatgtagaa ataggtactt ttaaaatgaa 420 tagatcctac tttaattgaa tttatcttgg agttagaata tcttgatttg gattttagtt 480 ctgctacttc ttaattacat tacttggtaa ggccacttgt gaagtcagtc tctttggagg 540 aatattattt atctataagg ctgttacaat tactgaattt taaaaaatgt gtatttattt 600 t 601 70 601 DNA Homo sapiens 70 tagtaattta ttaaaaatgt agaaataggt acttttaaaa tgaatagatc ctactttaat 60 tgaatttatc ttggagttag aatatcttga tttggatttt agttctgcta cttcttaatt 120 acattacttg gtaaggccac ttgtgaagtc agtctctttg gaggaatatt atttatctat 180 aaggctgtta caattactga attttaaaaa atgtgtattt attttttaat gtatttgtta 240 catttttagt attgatgttg ggataggcat ttaagcaagt ctataactca cctacatgca 300 yaattttgcc ttaatcagtt taaagctttc tcttaaatga gagatttgaa attcataatt 360 tctgtggttc ttatcagttc tgagttttat tttttgccct ttttattttt ttaaaggaaa 420 aattgaggct tcagaaattg tccagtctct ccagacactg ggtctgacta tttctgaaca 480 acaagcagag ttgattcttc aaaggtaagc tcttcatgtt ggtcaacaat tgactttcac 540 tttaatatcc tgcattagaa ctctgtgttt gtaagtgtgg ctttaaaaca cctccctagt 600 c 601 71 601 DNA Homo sapiens 71 gagttagaat atcttgattt ggattttagt tctgctactt cttaattaca ttacttggta 60 aggccacttg tgaagtcagt ctctttggag gaatattatt tatctataag gctgttacaa 120 ttactgaatt ttaaaaaatg tgtatttatt ttttaatgta tttgttacat ttttagtatt 180 gatgttggga taggcattta agcaagtcta taactcacct acatgcataa ttttgcctta 240 atcagtttaa agctttctct taaatgagag atttgaaatt cataatttct gtggttctta 300 ycagttctga gttttatttt ttgccctttt tattttttta aaggaaaaat tgaggcttca 360 gaaattgtcc agtctctcca gacactgggt ctgactattt ctgaacaaca agcagagttg 420 attcttcaaa ggtaagctct tcatgttggt caacaattga ctttcacttt aatatcctgc 480 attagaactc tgtgtttgta agtgtggctt taaaacacct ccctagtctt cattatgtat 540 atccaagatc tttttgtctt ttttcctccc attcattttg tatgtgtaca tttatctaaa 600 g 601 72 601 DNA Homo sapiens 72 gtattgatgt tgggataggc atttaagcaa gtctataact cacctacatg cataattttg 60 ccttaatcag tttaaagctt tctcttaaat gagagatttg aaattcataa tttctgtggt 120 tcttatcagt tctgagtttt attttttgcc ctttttattt ttttaaagga aaaattgagg 180 cttcagaaat tgtccagtct ctccagacac tgggtctgac tatttctgaa caacaagcag 240 agttgattct tcaaaggtaa gctcttcatg ttggtcaaca attgactttc actttaatat 300 yctgcattag aactctgtgt ttgtaagtgt ggctttaaaa cacctcccta gtcttcatta 360 tgtatatcca agatcttttt gtcttttttc ctcccattca ttttgtatgt gtacatttat 420 ctaaagtgta agaatgggaa gtgtaagctc agactggact ctttctttca aggcctcaaa 480 ggatagtgga atggcaggaa gtaaggtttt aactccatag atgaggagct gaagagtttt 540 ggtgttgctt tttctccatt tgatttctaa tgtgacagta aaactcattg attcaaacta 600 a 601 73 601 DNA Homo sapiens 73 cattgattca aactaagaag actagcagat tcatcacatt atttaaccta gatgtgactg 60 gaaaaaaggg aaattactaa gctctccaag ctaacaaaga aatacctgtt taaactttca 120 gaaaacagaa atgcaaattt gaaccttatt gtctggggca atcagtttga ctatttaagt 180 cagactttta tactcttaat gttttgtttc atgggataga gcagtaatct ctgcagccca 240 ggtgctctca aatactctgt tgctataaac acagggcagg aactgatttt ttatgataac 300 rtaaaacaga aaaggacaat tatattgtat taatattgtt gtgaatattt tcagtcctca 360 cattgtctaa aaatctttct aaatggcttt gttattgaat ttatctcatt ttatatctgt 420 gccaacagca ttttcatcct ttctcttcat aatttctttt acaaacagct gctcaagagg 480 aaggctcaaa gtctcaaggc tgagcacgta atgacttttg ttagtactag atgagaaggg 540 ctttcctgag gaaatgaaaa cctaaaacat gaaaagaaga taaacagaat ttggacagtg 600 a 601 74 601 DNA Homo sapiens variation (301)...(301) ′A′ may be either present or absent 74 aaactaagaa gactagcaga ttcatcacat tatttaacct agatgtgact ggaaaaaagg 60 gaaattacta agctctccaa gctaacaaag aaatacctgt ttaaactttc agaaaacaga 120 aatgcaaatt tgaaccttat tgtctggggc aatcagtttg actatttaag tcagactttt 180 atactcttaa tgttttgttt catgggatag agcagtaatc tctgcagccc aggtgctctc 240 aaatactctg ttgctataaa cacagggcag gaactgattt tttatgataa cgtaaaacag 300 aaaaggacaa ttatattgta ttaatattgt tgtgaatatt ttcagtcctc acattgtcta 360 aaaatctttc taaatggctt tgttattgaa tttatctcat tttatatctg tgccaacagc 420 attttcatcc tttctcttca taatttcttt tacaaacagc tgctcaagag gaaggctcaa 480 agtctcaagg ctgagcacgt aatgactttt gttagtacta gatgagaagg gctttcctga 540 ggaaatgaaa acctaaaaca tgaaaagaag ataaacagaa tttggacagt gagatataga 600 g 601 75 601 DNA Homo sapiens 75 cagaaatgca aatttgaacc ttattgtctg gggcaatcag tttgactatt taagtcagac 60 ttttatactc ttaatgtttt gtttcatggg atagagcagt aatctctgca gcccaggtgc 120 tctcaaatac tctgttgcta taaacacagg gcaggaactg attttttatg ataacgtaaa 180 acagaaaagg acaattatat tgtattaata ttgttgtgaa tattttcagt cctcacattg 240 tctaaaaatc tttctaaatg gctttgttat tgaatttatc tcattttata tctgtgccaa 300 yagcattttc atcctttctc ttcataattt cttttacaaa cagctgctca agaggaaggc 360 tcaaagtctc aaggctgagc acgtaatgac ttttgttagt actagatgag aagggctttc 420 ctgaggaaat gaaaacctaa aacatgaaaa gaagataaac agaatttgga cagtgagata 480 tagagcatat aatattctgc ttctaaagta atattcttct aggaaagtga gggcgtttcc 540 ctggctgtta ggccagaaat catattccta tattttcttt gatagcttta ggaataatgc 600 a 601 76 601 DNA Homo sapiens variation (301)...(301) T may be either present or absent 76 tgaaccttat tgtctggggc aatcagtttg actatttaag tcagactttt atactcttaa 60 tgttttgttt catgggatag agcagtaatc tctgcagccc aggtgctctc aaatactctg 120 ttgctataaa cacagggcag gaactgattt tttatgataa cgtaaaacag aaaaggacaa 180 ttatattgta ttaatattgt tgtgaatatt ttcagtcctc acattgtcta aaaatctttc 240 taaatggctt tgttattgaa tttatctcat tttatatctg tgccaacagc attttcatcc 300 tttctcttca taatttcttt tacaaacagc tgctcaagag gaaggctcaa agtctcaagg 360 ctgagcacgt aatgactttt gttagtacta gatgagaagg gctttcctga ggaaatgaaa 420 acctaaaaca tgaaaagaag ataaacagaa tttggacagt gagatataga gcatataata 480 ttctgcttct aaagtaatat tcttctagga aagtgagggc gtttccctgg ctgttaggcc 540 agaaatcata ttcctatatt ttctttgata gctttaggaa taatgcaaat tctaagccca 600 a 601 77 601 DNA Homo sapiens variation (301)...(301) C, T, or neither (single base deletion) may be present. 77 gaaccttatt gtctggggca atcagtttga ctatttaagt cagactttta tactcttaat 60 gttttgtttc atgggataga gcagtaatct ctgcagccca ggtgctctca aatactctgt 120 tgctataaac acagggcagg aactgatttt ttatgataac gtaaaacaga aaaggacaat 180 tatattgtat taatattgtt gtgaatattt tcagtcctca cattgtctaa aaatctttct 240 aaatggcttt gttattgaat ttatctcatt ttatatctgt gccaacagca ttttcatcct 300 ytctcttcat aatttctttt acaaacagct gctcaagagg aaggctcaaa gtctcaaggc 360 tgagcacgta atgacttttg ttagtactag atgagaaggg ctttcctgag gaaatgaaaa 420 cctaaaacat gaaaagaaga taaacagaat ttggacagtg agatatagag catataatat 480 tctgcttcta aagtaatatt cttctaggaa agtgagggcg tttccctggc tgttaggcca 540 gaaatcatat tcctatattt tctttgatag ctttaggaat aatgcaaatt ctaagcccaa 600 g 601 78 601 DNA Homo sapiens variation (301)...(301) C may be either present or absent 78 accttattgt ctggggcaat cagtttgact atttaagtca gacttttata ctcttaatgt 60 tttgtttcat gggatagagc agtaatctct gcagcccagg tgctctcaaa tactctgttg 120 ctataaacac agggcaggaa ctgatttttt atgataacgt aaaacagaaa aggacaatta 180 tattgtatta atattgttgt gaatattttc agtcctcaca ttgtctaaaa atctttctaa 240 atggctttgt tattgaattt atctcatttt atatctgtgc caacagcatt ttcatccttt 300 ctcttcataa tttcttttac aaacagctgc tcaagaggaa ggctcaaagt ctcaaggctg 360 agcacgtaat gacttttgtt agtactagat gagaagggct ttcctgagga aatgaaaacc 420 taaaacatga aaagaagata aacagaattt ggacagtgag atatagagca tataatattc 480 tgcttctaaa gtaatattct tctaggaaag tgagggcgtt tccctggctg ttaggccaga 540 aatcatattc ctatattttc tttgatagct ttaggaataa tgcaaattct aagcccaagc 600 t 601 79 601 DNA Homo sapiens 79 atattttcag tcctcacatt gtctaaaaat ctttctaaat ggctttgtta ttgaatttat 60 ctcattttat atctgtgcca acagcatttt catcctttct cttcataatt tcttttacaa 120 acagctgctc aagaggaagg ctcaaagtct caaggctgag cacgtaatga cttttgttag 180 tactagatga gaagggcttt cctgaggaaa tgaaaaccta aaacatgaaa agaagataaa 240 cagaatttgg acagtgagat atagagcata taatattctg cttctaaagt aatattcttc 300 haggaaagtg agggcgtttc cctggctgtt aggccagaaa tcatattcct atattttctt 360 tgatagcttt aggaataatg caaattctaa gcccaagctt cagaatagac taagaagtat 420 tagcttagct gccatgacaa aataccatag gctggatgca ttaaacaatg gaaatttagt 480 ttttcacagg tctgggagct gggaagttta agatgagagt gccagcatgg ttgggttgta 540 gtgagggctc tctttctggc ttgcagatag accccttctc actgtattgt catatggcag 600 a 601 80 601 DNA Homo sapiens 80 cattgtctaa aaatctttct aaatggcttt gttattgaat ttatctcatt ttatatctgt 60 gccaacagca ttttcatcct ttctcttcat aatttctttt acaaacagct gctcaagagg 120 aaggctcaaa gtctcaaggc tgagcacgta atgacttttg ttagtactag atgagaaggg 180 ctttcctgag gaaatgaaaa cctaaaacat gaaaagaaga taaacagaat ttggacagtg 240 agatatagag catataatat tctgcttcta aagtaatatt cttctaggaa agtgagggcg 300 kttccctggc tgttaggcca gaaatcatat tcctatattt tctttgatag ctttaggaat 360 aatgcaaatt ctaagcccaa gcttcagaat agactaagaa gtattagctt agctgccatg 420 acaaaatacc ataggctgga tgcattaaac aatggaaatt tagtttttca caggtctggg 480 agctgggaag tttaagatga gagtgccagc atggttgggt tgtagtgagg gctctctttc 540 tggcttgcag atagacccct tctcactgta ttgtcatatg gcagagagag agagagagag 600 a 601 81 601 DNA Homo sapiens variation (301)...(301) A, G, or neither (single base deletion) may be present 81 gaaagtgagg gcgtttccct ggctgttagg ccagaaatca tattcctata ttttctttga 60 tagctttagg aataatgcaa attctaagcc caagcttcag aatagactaa gaagtattag 120 cttagctgcc atgacaaaat accataggct ggatgcatta aacaatggaa atttagtttt 180 tcacaggtct gggagctggg aagtttaaga tgagagtgcc agcatggttg ggttgtagtg 240 agggctctct ttctggcttg cagatagacc ccttctcact gtattgtcat atggcagaga 300 ragagagaga gagagagaga gagagagaga ggggatcttt ctcttgcttt ctattataag 360 gccatagtcc tgttggatca gggttccatt cttatgactt tatttgactt taccccccta 420 agatgctatc tccagatata atcacacggt gggttagggc ctcaacattt ggatttggga 480 gggacacagc tcagtccata gcaaaggata atgcagaggg ttggatattt aaaagtagct 540 acacaatttt taatataaat attttatggt aacttttttt tttttttgag atggagtcta 600 g 601 82 601 DNA Homo sapiens 82 atctttctct tgctttctat tataaggcca tagtcctgtt ggatcagggt tccattctta 60 tgactttatt tgactttacc cccctaagat gctatctcca gatataatca cacggtgggt 120 tagggcctca acatttggat ttgggaggga cacagctcag tccatagcaa aggataatgc 180 agagggttgg atatttaaaa gtagctacac aatttttaat ataaatattt tatggtaact 240 tttttttttt tttgagatgg agtctagctc tgttgcccag gctggagcgc aatggtgcga 300 dctcagctca ctgcaacctc cgcctcccag gttcaagcaa ttctcctgcc tcagcctcct 360 gagtagttgg gactataggc acgcgccacc acgcctggct attttttttt tatttttact 420 agagacgggt ttgcaccata ttggtcaggc ttgtctcgaa ctcctgacat caggtgatcc 480 acccatcttg gcctcccaaa gtgctgggat tacagaagtg agccaccgcg cctagccagc 540 agctttactg agatgtaatt cacatgccat aaattcactt ttctaaagta tacaattcag 600 t 601 83 601 DNA Homo sapiens variation (301)...(301) T may be either present or absent 83 atataatcac acggtgggtt agggcctcaa catttggatt tgggagggac acagctcagt 60 ccatagcaaa ggataatgca gagggttgga tatttaaaag tagctacaca atttttaata 120 taaatatttt atggtaactt tttttttttt ttgagatgga gtctagctct gttgcccagg 180 ctggagcgca atggtgcgat ctcagctcac tgcaacctcc gcctcccagg ttcaagcaat 240 tctcctgcct cagcctcctg agtagttggg actataggca cgcgccacca cgcctggcta 300 tttttttttt atttttacta gagacgggtt tgcaccatat tggtcaggct tgtctcgaac 360 tcctgacatc aggtgatcca cccatcttgg cctcccaaag tgctgggatt acagaagtga 420 gccaccgcgc ctagccagca gctttactga gatgtaattc acatgccata aattcacttt 480 tctaaagtat acaattcagt gacttaaaac atttatttat ttttaaattg acagaattac 540 atgtatttat catgtacaac atgatgtttt gaagtatatg tacattgtgg agtgactaag 600 t 601 84 601 DNA Homo sapiens 84 ttctcttagt atttttcaag aatataatat attattatta attgtagtct tcatgttgta 60 tagtggagct cttgaactta ttcctcatgt caagctgaaa ttgtgtgtcc tttaacacaa 120 accatacccg actcccaaag tattctgctc tctgcttcta tgagattaac tttttctgat 180 tccacatgag tgagatcatg cagtatttat ttgtctttac ctggcttatt tcattcatat 240 tgttacagat aacaggattt ccttcttttt ttaatggccg aatagttttc tattgtatat 300 rtatagcaca ttttctctct tcatgcattg gtggacactt aggttgattc cgtatcttgg 360 ctatcgtgaa tagtgctata atgaacatgg gaatgcacat ggctctttga catattgatt 420 tcattttata tatgtgtata tatatatgta tacacacaca tacatacagt ggtgggattg 480 caggatcata tggtagttct atatttaatt tttaaaggaa ctccatactg ctttccataa 540 tggctgtatt agtttaactc ctcaccaaca gggtgcaaaa gttccctttt ctctacatac 600 t 601 85 601 DNA Homo sapiens 85 tttgttctag agtatagttt aagtctgatg tttcttactg attttctgtt gagatgattt 60 gtctattgct gaaggtaggg tgttgaagtc ccctactatt gctgtattgc agtctctctc 120 tcctttcaga cgtattaatg gtttttattt tattttattt gttgttgttg ttgttgttgt 180 tgttgttttt gagacggagt ctcactctgt caccaggctg gagtgcagtg gcagggtctc 240 ggctcactgc agcccccgtc tcacggttca agcgattctc ctgcctcagc ctcccgagtc 300 rctgggacta caggcgcatg ccaccacgcc cagctaattt ttgtattttt agtaaagacg 360 gggtttcacc atgttggcca ggatggtctt gatctcttga cttcatgatc cacccgcctt 420 ggcctcccaa agtgctggga ttacaggtgt gagccaccac ccctggccaa tgtttggtat 480 ttatctttag gtgctctgat gttgggttca tatatattta taaaaaacaa tagctacata 540 acttattaag ggatatgcaa tataaaatat ataaattgtg acactgaaaa tttaaaatgg 600 g 601 86 601 DNA Homo sapiens 86 tctgatgttt cttactgatt ttctgttgag atgatttgtc tattgctgaa ggtagggtgt 60 tgaagtcccc tactattgct gtattgcagt ctctctctcc tttcagacgt attaatggtt 120 tttattttat tttatttgtt gttgttgttg ttgttgttgt tgtttttgag acggagtctc 180 actctgtcac caggctggag tgcagtggca gggtctcggc tcactgcagc ccccgtctca 240 cggttcaagc gattctcctg cctcagcctc ccgagtcgct gggactacag gcgcatgcca 300 ycacgcccag ctaatttttg tatttttagt aaagacgggg tttcaccatg ttggccagga 360 tggtcttgat ctcttgactt catgatccac ccgccttggc ctcccaaagt gctgggatta 420 caggtgtgag ccaccacccc tggccaatgt ttggtattta tctttaggtg ctctgatgtt 480 gggttcatat atatttataa aaaacaatag ctacataact tattaaggga tatgcaatat 540 aaaatatata aattgtgaca ctgaaaattt aaaatgggag gagtggagta aaagtacctt 600 c 601 87 601 DNA Homo sapiens 87 agtgctggga ttacaggtgt gagccaccac ccctggccaa tgtttggtat ttatctttag 60 gtgctctgat gttgggttca tatatattta taaaaaacaa tagctacata acttattaag 120 ggatatgcaa tataaaatat ataaattgtg acactgaaaa tttaaaatgg gaggagtgga 180 gtaaaagtac cttcatataa cttactatta tatcctctta ttgaattgac ccttttatca 240 ttatatagga actttgtttc tcctttacaa cttctgactt aaagtttgtt ttatatgata 300 yaagtaaagt tactcctgct ctcctttggt ttctgtttcc atggaatatc tttttccatt 360 ccttcaccat cagtctgtgt gtatttttac agatgaaatg agtctgtcat gggcagcata 420 tagttggatc tagttttttt aatccactca gacactgtgt tttttgattg gataatttaa 480 tccattcatg ttcaaggtaa ttattgataa gtaaggactt tgtactacca ttttgcttat 540 tgtttcatgg ttcttttata gatcctttat tcttttcttc ctctcttgct gtcttttttt 600 t 601 88 601 DNA Homo sapiens 88 ggtttttggt ttgtggttac caagaggtta caaaaaacat cttaagagtt ataatagttt 60 attttaactt gataacttaa tttttattgc aaaaaccccc caaaacaaaa aaatctacac 120 ttttacttaa tcccctgaaa ttttgaattt ttgatgtcac agtttacctc ttttcatatt 180 gtgtatccct taaattattg tagctattat tacttttaat agttttctct ttcctactac 240 agatgtaagt gatttgcata ccatcattac agtattattt tgaatttacc tgtgtacttt 300 yttttatcag ccagttttat actttcagat gtttttgtgt tactcattag catctttttc 360 tttcagcttg aggagctcct tttacgtttc ttataaaata ggtgcggtca tgattatctc 420 cctcagctat tgtttgtctg ggaaagtatc tctccttcat ttctgaagga cactttgctg 480 ggtacattac ccttggttgg tatttttctc cttgaacgct ttaaatatat catccctttc 540 tctcctgacc tgttaggtct ctgctgacca gtctgtttcc aaccatattg ggactgtctt 600 a 601 89 601 DNA Homo sapiens 89 attttaacca tccattgttt ctgcttctct agataaccct gactaatata taattggtat 60 gaagtgatat ctcatggctt tgatttatat ttctttcatg gctagtgact ttttttgtac 120 ttttgggata ttgttattat tattattatt attactagtg tttatacttc ttcagtaaaa 180 gtgttagaaa caatttttaa aggcagaatg tgaccagagt ttcctgtagt tatataacca 240 tcatggacct tccctcaagt gctaagccat tagtgttact catgtcactc caaatgtcag 300 sttgttttct tccatttcac tgtctctttg tgtcccaaac ttgaattcat gggaaaaaca 360 tctgaatggt gcttaatatg gtttggatat ttgtcccctc caaatctcat gttgaaatat 420 gacctccagt gttggaagta gggactactt gggtcacgag agtggatcct tcattaatgg 480 cttggtaata agtgaactct attagttcat gaaagctggt tgttgataag agcctggcat 540 ctcatttctc ttgtccttct ctcaccatct gacacacttg ctcacctttt ttcttcagcc 600 a 601 90 601 DNA Homo sapiens 90 ttccagagtg tagaagtaca ctgtcctatc ctttctagga gatcattata acaccaaaag 60 cagacagtat atgaaacagg gaaattagag gccaagatac ctatgactta tatgtaaaaa 120 tttaaagaaa atattagcaa actgaatcag ccattttaaa aaatatacca caatcaatgc 180 attcataaga gcagcttaac aaaatttgtt agaaggcatt aaagaagact cagtatagaa 240 aagatgtacc ttctctccaa attggtgata gagattcaat gccattaaaa aaacccacct 300 kgtttttttg aggaacttgt caagctgagt ctcaaattta tatcaaagag caaaggccta 360 agaatatcca ggacattcct gaagaactgt aaggagccag gggcctgccc tatcagatac 420 caagggttgt tattaagcca taaccaagtc agtgctgttt ctacagaaac agacaagtta 480 acaagtgaaa cataatagag agcccagaaa cagacccatc catattttgg atttgtcacg 540 tgaaagaagt agctttgcaa aactttggga aaaggagagt gtgtgcaata gatgatgctc 600 g 601 91 601 DNA Homo sapiens 91 taaagaagac tcagtataga aaagatgtac cttctctcca aattggtgat agagattcaa 60 tgccattaaa aaaacccacc tggttttttt gaggaacttg tcaagctgag tctcaaattt 120 atatcaaaga gcaaaggcct aagaatatcc aggacattcc tgaagaactg taaggagcca 180 ggggcctgcc ctatcagata ccaagggttg ttattaagcc ataaccaagt cagtgctgtt 240 tctacagaaa cagacaagtt aacaagtgaa acataataga gagcccagaa acagacccat 300 mcatattttg gatttgtcac gtgaaagaag tagctttgca aaactttggg aaaaggagag 360 tgtgtgcaat agatgatgct cgtgctcatg cagacaaaaa ggaaattggg atacctgcct 420 cttaccgtac acaaacacca acctaaacgt gaaagttaaa ctataacagc ttgaggtggt 480 ggggaagaaa tatctttatc tcagtgtagg gaagaattta ttttaaaaag aagacacaaa 540 aggccataca taggaatgaa aagattgaat tcagctgcat taaaaagatt aaattcagct 600 g 601 92 601 DNA Homo sapiens 92 tatctttatc tcagtgtagg gaagaattta ttttaaaaag aagacacaaa aggccataca 60 taggaatgaa aagattgaat tcagctgcat taaaaagatt aaattcagct gcgttaaaat 120 caagagcatc tgtacttgga cagcatagag tggaaagaca aagagaaggt atttgccagc 180 ttataacttg aaggattaga atgaatgata taaagaacta tgtaaataag aaaaagacat 240 acaaccggtt agaaaaacgg gcaaagacat gaacagcata tttcacgtga aggaaacagc 300 rgtagcaaat gaacatggta agagatgctc aacacgttta gtaatttgaa gggaaatgca 360 agttataccc acagcaagac tatcttatct aggaagtttg tcaataccct aaatgttctg 420 tggttttaag ctacagagtt tgtaattcat ttatttattc aataaatact cagtggcagg 480 cactgtttta gaaaccttgg ttataacttt gaatgaaatt aaaaaaaatc cttgccttgt 540 ggaggatgct tatgtgtggg gagttgggtg gtggggtcaa acaacaatta cattaaaata 600 g 601 93 601 DNA Homo sapiens 93 acttgaagga ttagaatgaa tgatataaag aactatgtaa ataagaaaaa gacatacaac 60 cggttagaaa aacgggcaaa gacatgaaca gcatatttca cgtgaaggaa acagcggtag 120 caaatgaaca tggtaagaga tgctcaacac gtttagtaat ttgaagggaa atgcaagtta 180 tacccacagc aagactatct tatctaggaa gtttgtcaat accctaaatg ttctgtggtt 240 ttaagctaca gagtttgtaa ttcatttatt tattcaataa atactcagtg gcaggcactg 300 ktttagaaac cttggttata actttgaatg aaattaaaaa aaatccttgc cttgtggagg 360 atgcttatgt gtggggagtt gggtggtggg gtcaaacaac aattacatta aaatagaaaa 420 tagtgacata aataaaccta taaatattgc aacccagagt tatattataa atgtaagtag 480 tgactaggac tctcatgcag atatacctct gtgctgggac aaatgaaagt ttaagtgtaa 540 tttcccatat gcaagtcaaa ataaaaagtg acactagaaa acacaataat gaatatctga 600 a 601 94 601 DNA Homo sapiens 94 ggcatttaag tattctgcca tagggaagtg taaaagttgt aggcttttac tttttatagg 60 tactatattg tccaaataat ctcagcacct catggttgct aaggatctgt gtccttgttt 120 ggtcagatta tgtttatctc tggcataagg cacttaacaa tattcattaa aggttacaga 180 atctttttgc ttcatctgct tagcatttca taccagtttg ttttccacca aactttcaaa 240 ttttgattgt ttcattaata ttctgcatac tgatgtaaac caagttctat tattgtgcaa 300 wctgctcctg aaacccttag gaactctctg aaggagtttt atttattttt tgtttttgtt 360 tttgtttttg ttttgttttt ttgagacgga gtcttgctct gttgcccagg ctagagtgca 420 gtggtgcgat ctcggctctc tgcaaactcg gcctccgggg ttcacgccat tctcctgcct 480 cagccaccgg agtagctggg actacaggca cccaccactg cgcctggcta attttttttg 540 tatttttagt agagacgggg tttcaccgtg ttagccagga tggtctcgat ctcctgacct 600 t 601 95 601 DNA Homo sapiens variation (301)...(301) T, C, or neither (single base deletion) may be present 95 ttgagacgga gtcttgctct gttgcccagg ctagagtgca gtggtgcgat ctcggctctc 60 tgcaaactcg gcctccgggg ttcacgccat tctcctgcct cagccaccgg agtagctggg 120 actacaggca cccaccactg cgcctggcta attttttttg tatttttagt agagacgggg 180 tttcaccgtg ttagccagga tggtctcgat ctcctgacct tgtaatccgc ccgcctcgcc 240 tcccaaagtg ctgggattac aggcgtgagc cactgtgccc ggcctttttt tttttttttt 300 ytttatgggc ttgtcttcta cacttcagat ttgactaaat taaatatgca ttaaatgaag 360 tcaggagttc acattgccac tagtaacaat gcctaagctt acataaagca ttataaaatt 420 gttggtgatt agtgccttct cagctatgag tataagataa tattatacta gtagttcagt 480 tgcctagata aattgtacac tatgtgaagt tttatttaca taattcttac ggtatttttt 540 aaggtagttg ataacagttg agactacaat tgtatctcca ttttattgat agtaaaatga 600 a 601 96 601 DNA Homo sapiens 96 gaattgtaaa aatattatta tagaattgtt tctctcaaac tatagtaatg tagaataggt 60 tgaaggggtg atgatttgaa acaatacctc tccattagct aaattttata tagaatctat 120 tgcatgtttt aaatgataag tcagatttat aaaaatattt ttataaacag taggaaatga 180 gtttaggggt attcacatac agttttaatt tttatttaca tatttaaaac atatcatggt 240 ataaatatga tgtggatata aatttgagat aaaggaagta ttgtttaaga attgatgaac 300 kaatttctta aaagatgtca tcaccagttg gttttctagc cttatgaaaa atggttgcaa 360 taaaaaagat tgactatgat aaaatgctgc cctttcattt taacctagac caagagaaaa 420 catactgtga atctatgatg aatgaaagaa agttgtaact gttggttttg tatatttgta 480 attactgttt attttcattt cttgtgaact gatactgtac tttgttcatt gtgagtagac 540 aacttataat ctatgtactc aaattggttt agtataaatt ctagggaatg aagttcatat 600 t 601 97 452 DNA Homo sapiens 97 tgttatactt atggtcaaca ctttttatat ttgtctgtag atttctgtac aaaaagattc 60 tgacactgtt ttaagccagc attccttcag aatgtaccca aatctcaaaa tttatttagg 120 ggcaaagcta atgctttaaa gaaaaaggag argggattgg tgtgtgtttt tctttaggaa 180 cagtagtaac ttgactttta gagaacttga ataagcattt attttttcct ttgtcctatt 240 ttattgtgaa gtttatttat ttaaaataaa atggatttct ctggaattta gtttctgcaa 300 atttgaggag tttccaaagt caaccttcag gtttgatact tctctagaaa gactcacata 360 actcactgaa agcttattac ccctggttat ggtttattac ggggaaaaga tgcggatgaa 420 aatcagtcaa gtaaagaagc acatagggca ga 452 98 601 DNA Homo sapiens 98 ttatatcatt ctgcttttat ttttaggttc acggttcaaa atcagacaaa atgaacatat 60 ttggtggctt tcgacagatg gtaaaagaag gaggtatccg ctcgctttgg aggggaaatg 120 gtacaaacgt catcaaaatt gctcctgaga cagctgttaa attctgggca tatgaacagg 180 taattgttat cacccgtgga atttattaac aaagaggagt tagtaaacgg attcaataaa 240 tgttaatgta taatgctttt gggattcttg ttttaataca tgataatctt tcacatatac 300 yccataagga ggatcactta taggagatta gactaaataa aatcagagat ttctcatgac 360 caagttatgg gattcttaat tcatcatatt atttataaag tttttttttt ctaagtagtt 420 cttaaaggaa gggtagaatt ttagtttatt cattctgaat cctgagcaga agcagcacac 480 taacataagt tttatgaaag tgtcacaatc taacctctgg aaggaaaact ataagttgaa 540 gtcctttgtg taatttgacg ttgctgtaaa attgagctga gtttggagtg acacctccat 600 g 601 99 601 DNA Homo sapiens 99 aaattgctcc tgagacagct gttaaattct gggcatatga acaggtaatt gttatcaccc 60 gtggaattta ttaacaaaga ggagttagta aacggattca ataaatgtta atgtataatg 120 cttttgggat tcttgtttta atacatgata atctttcaca tataccccat aaggaggatc 180 acttatagga gattagacta aataaaatca gagatttctc atgaccaagt tatgggattc 240 ttaattcatc atattattta taaagttttt tttttctaag tagttcttaa aggaagggta 300 kaattttagt ttattcattc tgaatcctga gcagaagcag cacactaaca taagttttat 360 gaaagtgtca caatctaacc tctggaagga aaactataag ttgaagtcct ttgtgtaatt 420 tgacgttgct gtaaaattga gctgagtttg gagtgacacc tccatgaagg caggggcgtg 480 gcttcttccc catgtactcc agcacctaga cagagcttgg catgtgataa gtttcaagcg 540 agtgttgaat gagtcaatga atgaacaaat gcatttacct ctgaatcact tctctgtcgg 600 c 601 100 601 DNA Homo sapiens 100 tgggattctt gttttaatac atgataatct ttcacatata ccccataagg aggatcactt 60 ataggagatt agactaaata aaatcagaga tttctcatga ccaagttatg ggattcttaa 120 ttcatcatat tatttataaa gttttttttt tctaagtagt tcttaaagga agggtagaat 180 tttagtttat tcattctgaa tcctgagcag aagcagcaca ctaacataag ttttatgaaa 240 gtgtcacaat ctaacctctg gaaggaaaac tataagttga agtcctttgt gtaatttgac 300 rttgctgtaa aattgagctg agtttggagt gacacctcca tgaaggcagg ggcgtggctt 360 cttccccatg tactccagca cctagacaga gcttggcatg tgataagttt caagcgagtg 420 ttgaatgagt caatgaatga acaaatgcat ttacctctga atcacttctc tgtcggcttt 480 tgttaacttg gattatttga gctattgctt cagcctaact caatgtaaag gggaaataca 540 gaggtaagtt ttagagtttg ggttctcttt atggtcatta gcagaactgt ctagttgagc 600 a 601 101 601 DNA Homo sapiens 101 catatacccc ataaggagga tcacttatag gagattagac taaataaaat cagagatttc 60 tcatgaccaa gttatgggat tcttaattca tcatattatt tataaagttt tttttttcta 120 agtagttctt aaaggaaggg tagaatttta gtttattcat tctgaatcct gagcagaagc 180 agcacactaa cataagtttt atgaaagtgt cacaatctaa cctctggaag gaaaactata 240 agttgaagtc ctttgtgtaa tttgacgttg ctgtaaaatt gagctgagtt tggagtgaca 300 sctccatgaa ggcaggggcg tggcttcttc cccatgtact ccagcaccta gacagagctt 360 ggcatgtgat aagtttcaag cgagtgttga atgagtcaat gaatgaacaa atgcatttac 420 ctctgaatca cttctctgtc ggcttttgtt aacttggatt atttgagcta ttgcttcagc 480 ctaactcaat gtaaagggga aatacagagg taagttttag agtttgggtt ctctttatgg 540 tcattagcag aactgtctag ttgagcagcc acagattatg ttttccatta tttattccat 600 c 601 102 601 DNA Homo sapiens 102 ataaggagga tcacttatag gagattagac taaataaaat cagagatttc tcatgaccaa 60 gttatgggat tcttaattca tcatattatt tataaagttt tttttttcta agtagttctt 120 aaaggaaggg tagaatttta gtttattcat tctgaatcct gagcagaagc agcacactaa 180 cataagtttt atgaaagtgt cacaatctaa cctctggaag gaaaactata agttgaagtc 240 ctttgtgtaa tttgacgttg ctgtaaaatt gagctgagtt tggagtgaca cctccatgaa 300 sgcaggggcg tggcttcttc cccatgtact ccagcaccta gacagagctt ggcatgtgat 360 aagtttcaag cgagtgttga atgagtcaat gaatgaacaa atgcatttac ctctgaatca 420 cttctctgtc ggcttttgtt aacttggatt atttgagcta ttgcttcagc ctaactcaat 480 gtaaagggga aatacagagg taagttttag agtttgggtt ctctttatgg tcattagcag 540 aactgtctag ttgagcagcc acagattatg ttttccatta tttattccat cattgtttat 600 c 601 103 601 DNA Homo sapiens variation (301)...(301) C may be either present or absent 103 gcacctagac agagcttggc atgtgataag tttcaagcga gtgttgaatg agtcaatgaa 60 tgaacaaatg catttacctc tgaatcactt ctctgtcggc ttttgttaac ttggattatt 120 tgagctattg cttcagccta actcaatgta aaggggaaat acagaggtaa gttttagagt 180 ttgggttctc tttatggtca ttagcagaac tgtctagttg agcagccaca gattatgttt 240 tccattattt attccatcat tgtttatcaa ggactgtaag ggccttgaaa ttcaactccc 300 ccccccatag tttttgtatt attccatgta gattttagat tattctggag agtgttttgt 360 tcttgagcaa cagaatactc ttgagaagat tacgaagtcc agtggtatcc ttttctttgc 420 ctaggaaata gagaagcaaa aaaaaaaaaa aaaaaaaatt aaagaaaatc tagtctccag 480 gattttaatt agaacctatc cttgggaagg ctattttcct tatatgaagg tttgaagatt 540 caaatcatga ttattaaggg ctaatgtttg agataccctt aggttattct gaccacatac 600 t 601 104 601 DNA Homo sapiens 104 catttacctc tgaatcactt ctctgtcggc ttttgttaac ttggattatt tgagctattg 60 cttcagccta actcaatgta aaggggaaat acagaggtaa gttttagagt ttgggttctc 120 tttatggtca ttagcagaac tgtctagttg agcagccaca gattatgttt tccattattt 180 attccatcat tgtttatcaa ggactgtaag ggccttgaaa ttcaactccc ccccccatag 240 tttttgtatt attccatgta gattttagat tattctggag agtgttttgt tcttgagcaa 300 sagaatactc ttgagaagat tacgaagtcc agtggtatcc ttttctttgc ctaggaaata 360 gagaagcaaa aaaaaaaaaa aaaaaaaatt aaagaaaatc tagtctccag gattttaatt 420 agaacctatc cttgggaagg ctattttcct tatatgaagg tttgaagatt caaatcatga 480 ttattaaggg ctaatgtttg agataccctt aggttattct gaccacatac ttggatttta 540 tgataggaaa gccacagcct aaaataaata aatactcaat gcagttattt cagtatgcaa 600 g 601 105 601 DNA Homo sapiens 105 gattattctg gagagtgttt tgttcttgag caacagaata ctcttgagaa gattacgaag 60 tccagtggta tccttttctt tgcctaggaa atagagaagc aaaaaaaaaa aaaaaaaaaa 120 attaaagaaa atctagtctc caggatttta attagaacct atccttggga aggctatttt 180 ccttatatga aggtttgaag attcaaatca tgattattaa gggctaatgt ttgagatacc 240 cttaggttat tctgaccaca tacttggatt ttatgatagg aaagccacag cctaaaataa 300 rtaaatactc aatgcagtta tttcagtatg caagaagttt ggtatttttg aaaaagtcca 360 tgggtattgc aagcaaatat gcacattttg ctttatgcca tttgtcagat tcttaccttg 420 gataccacca acaggcatcc tctgcttctg tccacccaag ctccttcctg agacctcttt 480 atagtattgt gatttctgca cactaacttt cttagacatg aagagaaagc tgtctacaca 540 gtgtggtgta gttttcttat gggctctgga cctatggtgc tgttttctct cctcctgctg 600 a 601 106 601 DNA Homo sapiens 106 tgaccacata cttggatttt atgataggaa agccacagcc taaaataaat aaatactcaa 60 tgcagttatt tcagtatgca agaagtttgg tatttttgaa aaagtccatg ggtattgcaa 120 gcaaatatgc acattttgct ttatgccatt tgtcagattc ttaccttgga taccaccaac 180 aggcatcctc tgcttctgtc cacccaagct ccttcctgag acctctttat agtattgtga 240 tttctgcaca ctaactttct tagacatgaa gagaaagctg tctacacagt gtggtgtagt 300 kttcttatgg gctctggacc tatggtgctg ttttctctcc tcctgctgaa ggtccattca 360 tccctcgggg ctctctaaaa gccaccttcc tgtgacaagc atatactaag catctcaatc 420 aaagccagtt cctcccctgt ccagcctccc tcgagtgctg aattgcagaa tatcccattt 480 ttcattggat gatggaaaac ccattgtttt cccagtggat tgtaaattac ttcggggtaa 540 ataggctgta tatattctca aatttcccag agtatgtaac taggtcactt ttagattcag 600 a 601 107 601 DNA Homo sapiens 107 tccatgggta ttgcaagcaa atatgcacat tttgctttat gccatttgtc agattcttac 60 cttggatacc accaacaggc atcctctgct tctgtccacc caagctcctt cctgagacct 120 ctttatagta ttgtgatttc tgcacactaa ctttcttaga catgaagaga aagctgtcta 180 cacagtgtgg tgtagttttc ttatgggctc tggacctatg gtgctgtttt ctctcctcct 240 gctgaaggtc cattcatccc tcggggctct ctaaaagcca ccttcctgtg acaagcatat 300 mctaagcatc tcaatcaaag ccagttcctc ccctgtccag cctccctcga gtgctgaatt 360 gcagaatatc ccatttttca ttggatgatg gaaaacccat tgttttccca gtggattgta 420 aattacttcg gggtaaatag gctgtatata ttctcaaatt tcccagagta tgtaactagg 480 tcacttttag attcagatag attttgttcc ttgaatagct agtactttag gaaactaaga 540 aaaagatctt ttcaacctgg tatgtagctc tgtcaaacac atcatcagta tggggtaaac 600 c 601 108 462 DNA Homo sapiens 108 ctcggggctc tctaaaagcc accttcctgt gacaagcata tactaagcat ctcaatcaaa 60 gccagttcct cccctgtcca gcctccctcg agtgctgaat tgcagaatat cccatttttc 120 attggatgat ggaaaaccca ttgttttccc agtggattgt aaattacttc ggggtaaata 180 ggctgtatat attctcaaat ttcccagagt atgtaactag gtcactttta gattcagata 240 gattttgttc cttgaatagc tagtacttta ggaaactaag aaaaagatct tttcaacctg 300 rtatgtagct ctgtcaaaca catcatcagt atggggtaaa cctgtgttct ctgtgggttg 360 tcattaccat agtagtgtca ttgtatcatt gacagtgtaa tagtgtgggg tagtgttctt 420 gtggtttcag ctgccactct gtactgactg ctttccactc ca 462 109 414 DNA Homo sapiens 109 atcttttcaa cctggtatgt agctctgtca aacacatcat cagtatgggg taaacctgtg 60 ttctctgtgg gttgtcatta ccatagtagt gtcattgtat cattgacagt gtartagtgt 120 ggggtagtgt tcttgtggtt tcagctgcca ctctgtactg actgctttcc actccaacat 180 cttcctcttt atctcaacac tgtaggtcta cctgtgtact gtgtgtttca gcatctctgc 240 ttgcatgacc caggagtgcc tcccactcaa tatggccacc atgcatggtc atctttctgc 300 tactccctgt ctcctgaccc tgctccagca acacagacag acacccttcc tctttctata 360 tgtcatatgg tggggaatgc cctttagtac ttactcagga gttagttcct ctgg 414 110 601 DNA Homo sapiens 110 cattaccata gtagtgtcat tgtatcattg acagtgtaat agtgtggggt agtgttcttg 60 tggtttcagc tgccactctg tactgactgc tttccactcc aacatcttcc tctttatctc 120 aacactgtag gtctacctgt gtactgtgtg tttcagcatc tctgcttgca tgacccagga 180 gtgcctccca ctcaatatgg ccaccatgca tggtcatctt tctgctactc cctgtctcct 240 gaccctgctc cagcaacaca gacagacacc cttcctcttt ctatatgtca tatggtgggg 300 ratgcccttt agtacttact caggagttag ttcctctggg aagccttctg ttctagtttc 360 cttttgttac agcactttca cattgaattc tgacgttctc tgtacttatc tgctttgtga 420 gactgtgagc ttccttaggc agtagctact tgtattctta gcaccttgcc cagtgccagg 480 aaacccttat taagtaaatg aaaagacaga actgacagac tggaattaga gctcaagctt 540 gcctcaatct caagccatta agatgaaggg gagccgggcg tggtggctca cgcctctaat 600 c 601 111 601 DNA Homo sapiens 111 atagtagtgt cattgtatca ttgacagtgt aatagtgtgg ggtagtgttc ttgtggtttc 60 agctgccact ctgtactgac tgctttccac tccaacatct tcctctttat ctcaacactg 120 taggtctacc tgtgtactgt gtgtttcagc atctctgctt gcatgaccca ggagtgcctc 180 ccactcaata tggccaccat gcatggtcat ctttctgcta ctccctgtct cctgaccctg 240 ctccagcaac acagacagac acccttcctc tttctatatg tcatatggtg gggaatgccc 300 bttagtactt actcaggagt tagttcctct gggaagcctt ctgttctagt ttccttttgt 360 tacagcactt tcacattgaa ttctgacgtt ctctgtactt atctgctttg tgagactgtg 420 agcttcctta ggcagtagct acttgtattc ttagcacctt gcccagtgcc aggaaaccct 480 tattaagtaa atgaaaagac agaactgaca gactggaatt agagctcaag cttgcctcaa 540 tctcaagcca ttaagatgaa ggggagccgg gcgtggtggc tcacgcctct aatcccagca 600 c 601 112 601 DNA Homo sapiens 112 ccagcctggg caacgtggca aaaccccatt tctacaaaaa atataaaaat tagttggacg 60 tgggggtgtg tgcctgtact caggatgctg aggtgggagg atcacttgag ctcgagaggc 120 agaggttgca gtgagctggg atcacaccat tgcaatctag cctgggtgat agaatgagac 180 cttgtctcaa aaaaaaaata aataaataaa taaaggggaa gataaggatt ggaaacagaa 240 ggagcagcat gtggacagaa atgtaggcac aagaaggcat cactcactga agagactgaa 300 rgtggttcac tgtgcctcaa gactggtgga gtgtgtttcc ggaaagataa tgatgaaaga 360 gctggacaga taaacagggg ccaaatgtaa taggagtctg gattttattc tgaatatggt 420 aggggctatt gtagcatctt atatagggaa gtgaaatgag tacattcaca tttaaggaat 480 atcaacctga aaaaagagtg gagacattgt tgggggagag tgaggtagac tagaggcagg 540 gagaatattt aaataattga ggtaagaaat gatgaacacc agtataaggt gatgtcttta 600 a 601 113 601 DNA Homo sapiens 113 tagactagag gcagggagaa tatttaaata attgaggtaa gaaatgatga acaccagtat 60 aaggtgatgt ctttaaggaa tggagaaggg aatgaactga gaaatatttt ggaagtagaa 120 tcaacagaac tcactgactg actggatatg gaggtgagaa agagaagagt caagaatgat 180 attctaattt ctaacttgag tgactgcatt caaagagaat acaatatcag gttccatttt 240 gtgcatgctg agtttgagat gtgtgggaca tgtacaggga gctgtccagt aagcaattgg 300 rtatatcagc tagccattaa gagagagatc tttgatagag aggttgttgc tgagttgagc 360 cattggaatg ggcaggatca ctcaagaaga gcttataaat gagaagaatt ctaggaataa 420 gtccaaaggg agaagtaaaa gaagaaactt gcaaaggaca ctgagaagaa atagctcgag 480 ggatgggaga aaatccagag agagggatgg cataggagtc agtggaagga aacggtttca 540 tgggggtcag tactactggg tagtgaatat aataagaata tcttttagga tttctcaacc 600 c 601 114 601 DNA Homo sapiens 114 tcagggtggt tttgagggct cagttaagtc tcctttagga aggttcagtt ctgtagcctt 60 ggcaagttac ttaaagtctc tgtgactatt acctcatctc taagatgggg actaagcttg 120 gtgacatagt tttacatacc aggcacagtg cctgactttt tggctctgtc ctgaagtctt 180 ccctttgtat atggtatgtt tcggggaata ggagcctcaa gcacttatcc tttaaatatt 240 tatcctccat cagtcactaa acgtttactc tgtacttttg ataggtgctg tgggggtcca 300 rggtataaaa ggtaccttca aagttactgt taaagtgcag gaaggttttt aagcaaatta 360 tgtttaatga ttttgacaat ctgacatgca ggaaaattaa tagggcctat gcagaagagg 420 agttttatgt aacactctgt agttcaggaa acagagccct tggaagcagt gatctctctg 480 gggaggaatg tctggtattt gggaatctca tgaaatgata atatacttaa tttttatcat 540 gagcagcaaa acacagattt gctaggagaa agtcatcgta tgttgttgca ttgggcactt 600 t 601 115 601 DNA Homo sapiens 115 gaggaacctc catgtcattt tccatagtaa ctagaccttt ttgtttttta acatttctat 60 caatgtacac caagattcca atttctccat gtcctcccca acaccattaa gtggggtggt 120 ggtctactac tattgctgtg ttgctgttta ttcctccctt cagttctgta agtgtttgct 180 tcatatattt aggagcttaa tattaggtcc atatgaagtt ataatttctt cctggtaaag 240 tgacccattt atcattatgt aatgtccatc tttgtctctt gtgacagttt gtgtcttaaa 300 rtctattttg tctgatgtaa ttatggccac cccttttctc tttgggttcc cgtttttatg 360 gaatatcttt ttccatcctt tcactttcag cttatgtgtg tccttagatc taaagtgagt 420 ctcatagata aggtatagtt gattctgtat gtgttattca ctcagcaatt tatatctttt 480 agttagggga tttaatccat ttacatttaa agcagttact gatagggaag gacttactgt 540 tgtcatttgg ctagctacct ttttatcttt gtcctgtggc ttttctgttt ttcccttcct 600 c 601 116 601 DNA Homo sapiens 116 catatattta ggagcttaat attaggtcca tatgaagtta taatttcttc ctggtaaagt 60 gacccattta tcattatgta atgtccatct ttgtctcttg tgacagtttg tgtcttaaaa 120 tctattttgt ctgatgtaat tatggccacc ccttttctct ttgggttccc gtttttatgg 180 aatatctttt tccatccttt cactttcagc ttatgtgtgt ccttagatct aaagtgagtc 240 tcatagataa ggtatagttg attctgtatg tgttattcac tcagcaattt atatctttta 300 rttaggggat ttaatccatt tacatttaaa gcagttactg atagggaagg acttactgtt 360 gtcatttggc tagctacctt tttatctttg tcctgtggct tttctgtttt tcccttcctc 420 tcttcctggc ttcttctgtg ttttgttgat tttttttttt tttgtagtga tatgttctga 480 ttcccttctc atttcccttt gtgtgcattc tatagatgct atttttgtgg ttaccattgc 540 aactacataa agcatactaa agttatagca acttatttta agctgtttac aacttaactt 600 c 601 117 601 DNA Homo sapiens 117 gactgaaatt cagacacatg cagtctgatt ctaaccctcc tgtctgccag ctctgatcca 60 gaactttgca tgactgatac ggctgataga ttgtctatgg ctgatagact gtcatttctg 120 acctaaaagt ctgatcattt tacatctgtt cagacatctt tgcagccttt cggtgtcagt 180 tccaaagttg ttagtgggaa tttcaaagcc tttaataatc tagccccact ttgttcactc 240 tctgtgtaat aaccacatac aacaattggc tgcatctcca tagcacatgg tactcctccc 300 rttgtcttgg ttgtgccagc aacactggtt ttcgctttct cttcctgctt gttgaggtca 360 tttccaaggc ccaggtcttt gtgctttttc ccaagcttcc cagagcttct tccatactcc 420 ccttacttcc tgagatttaa ctgttctctc ttcagcgctt gtctagtaag aaggaggcag 480 cagcagcact gtggggtggt ggaaagtgta ccagctttgg agtcagacca ttggatctca 540 gccctaccat tttctactta gattttttta ggacaaattt ctccatcttt ctaagcctcc 600 a 601 118 601 DNA Homo sapiens 118 tctagcccca ctttgttcac tctctgtgta ataaccacat acaacaattg gctgcatctc 60 catagcacat ggtactcctc ccgttgtctt ggttgtgcca gcaacactgg ttttcgcttt 120 ctcttcctgc ttgttgaggt catttccaag gcccaggtct ttgtgctttt tcccaagctt 180 cccagagctt cttccatact ccccttactt cctgagattt aactgttctc tcttcagcgc 240 ttgtctagta agaaggaggc agcagcagca ctgtggggtg gtggaaagtg taccagcttt 300 rgagtcagac cattggatct cagccctacc attttctact tagatttttt taggacaaat 360 ttctccatct ttctaagcct ccaattgctc acttacaaaa ttgatataac atttaccttg 420 caagattggt atggaaggta attaacccag tatttagaac atagtaatta ataaataact 480 attattacca tcattactat agttaggaca ctcactgtta ggtgctatac aaagaggatc 540 ataaaaggga tgttgtcttg ggcttcttgg aataaatgtt gtccttttac tgtattttag 600 a 601 119 601 DNA Homo sapiens 119 ttggatctca gccctaccat tttctactta gattttttta ggacaaattt ctccatcttt 60 ctaagcctcc aattgctcac ttacaaaatt gatataacat ttaccttgca agattggtat 120 ggaaggtaat taacccagta tttagaacat agtaattaat aaataactat tattaccatc 180 attactatag ttaggacact cactgttagg tgctatacaa agaggatcat aaaagggatg 240 ttgtcttggg cttcttggaa taaatgttgt ccttttactg tattttagaa tatcattctg 300 rgtcataatt gtttgttgtc ataataatga aacatacttg aatattaaat taccctcttt 360 ttttattttt tagccatgtt agaaggttcc ccacagctga atatggttgg cctctttcga 420 cgaattattt ccaaagaagg aataccagga ctttacagag gcatcacccc aaacttcatg 480 aaggtgctcc ctgctgtagg catcagttat gtggtttatg aaaatatgaa gcaaacttta 540 ggagtaaccc agaaatgatg ttgcattttt tgctttagcc tgataattga aactttcaac 600 a 601 120 601 DNA Homo sapiens 120 atgaagcaaa ctttaggagt aacccagaaa tgatgttgca ttttttgctt tagcctgata 60 attgaaactt tcaacaatct ctggagtgac tttttctcct cgaattgaaa caagtctatg 120 gcaaaagaag ctgcattttt ttcacaaaag ggaagatggt aacaatggtc acttcaaact 180 tttgggctaa attatatgta cacagaaatg ttcaaaatca tagttttaat gtgttttgaa 240 aaggccacac aattatactt tatcttttct taataatcct gcaaatctct gccctgaatc 300 ygaaatctga aaatgtactg gcttgaacaa aatttgtttt gtgtgttaga gttataaatc 360 attaatcttt atttcgggtg gtttacgttt atgccagttc ctttatattt aaatttcttg 420 ttttatatat tttgaatgtc tttatagatt tctttaaatt tccttataga accattaata 480 gaaaatcatt acatttaaaa tataccttac agcaaaagca tccaaataag tatagggttt 540 atgtccttat ttttctttca gctgaatacg aatgagcaca gtggtggaat ttctgaaggg 600 a 601 121 601 DNA Homo sapiens 121 atcctgcaaa tctctgccct gaatccgaaa tctgaaaatg tactggcttg aacaaaattt 60 gttttgtgtg ttagagttat aaatcattaa tctttatttc gggtggttta cgtttatgcc 120 agttccttta tatttaaatt tcttgtttta tatattttga atgtctttat agatttcttt 180 aaatttcctt atagaaccat taatagaaaa tcattacatt taaaatatac cttacagcaa 240 aagcatccaa ataagtatag ggtttatgtc cttatttttc tttcagctga atacgaatga 300 rcacagtggt ggaatttctg aagggaagtg atgaaattat atttatttca gtgggcactt 360 ttccatttta ccactgtacc attatttggt tcctggagtt atacactaat tttcagtata 420 ttactgttaa attaccaaca caaggcaatt tatttgaaag attccgttta tcctgccatt 480 gctttgaaaa gcagcaggaa acgaaatcct ttgacttgta tcagcttctg cagagcatct 540 ttgttttcct ttgtcctttg tttcctacct tttgaatcag attccgtttt agtcaggaag 600 a 601 122 601 DNA Homo sapiens 122 cactgtacca ttatttggtt cctggagtta tacactaatt ttcagtatat tactgttaaa 60 ttaccaacac aaggcaattt atttgaaaga ttccgtttat cctgccattg ctttgaaaag 120 cagcaggaaa cgaaatcctt tgacttgtat cagcttctgc agagcatctt tgttttcctt 180 tgtcctttgt ttcctacctt ttgaatcaga ttccgtttta gtcaggaaga cttcttggga 240 ccattcttag taacctgaaa tttctttttt aattgcatga agtggattga tcatgagcaa 300 rtgatgtgct tatttctccc tcactgttga atatctttga acttgctgtt ttcaatatgg 360 gcagcacaaa ggtgagagat acatattaat agtagtatgt attactctta tacattagat 420 acctatattt aaatgaaagg cccaatttgt aaacatatac attcatattc tctcttgccc 480 caagttttag gaacatgtta ggatatagga gacttaattt ataataatga gagcattttt 540 ttattttact aaagccattt ttatagtcaa ctatcttttc ttatttgtgt gattagaact 600 t 601 123 601 DNA Homo sapiens 123 atagtagtat gtattactct tatacattag atacctatat ttaaatgaaa ggcccaattt 60 gtaaacatat acattcatat tctctcttgc cccaagtttt aggaacatgt taggatatag 120 gagacttaat ttataataat gagagcattt ttttatttta ctaaagccat ttttatagtc 180 aactatcttt tcttatttgt gtgattagaa cttagaaaaa tatttactag ttgaagttat 240 tatcagtttt taatttagtt cttaaactca tttcacttct aataatttct gttataaatt 300 kccagcattt taatgaaaat ctaatgatgt aataggcatt ttctttattt gaacctacct 360 cttttatttt ctgaaccaaa gagaaagatg gactggtgtt tgtgaaacat ttttaaaaat 420 gtagtttcat ttatattagt tatgtttgat aaatgtctca gtatttttat aatatgataa 480 gcctgggatt ctacttttag ggttatttgt acttttgagt aatatataaa gtgacaatat 540 taaggtacat gatcagctct ttctattttt actcgtaaaa attatggaaa tgaataattt 600 t 601 124 601 DNA Homo sapiens 124 atttctgtta taaattgcca gcattttaat gaaaatctaa tgatgtaata ggcattttct 60 ttatttgaac ctacctcttt tattttctga accaaagaga aagatggact ggtgtttgtg 120 aaacattttt aaaaatgtag tttcatttat attagttatg tttgataaat gtctcagtat 180 ttttataata tgataagcct gggattctac ttttagggtt atttgtactt ttgagtaata 240 tataaagtga caatattaag gtacatgatc agctctttct atttttactc gtaaaaatta 300 yggaaatgaa taattttgct aacaactttg aaatttcaaa cttctggaaa atatgaaaat 360 attcattgtt cattatgaat ttaaattgta aggtatgaat gtgatttgtc tgtacatctt 420 gtatcttttc caaaaaatga ttctgtatct tttggaaaaa agccgagagt tgaagatagt 480 atatttctgg tagtactgaa tatttactta cagtttctat caaaaatata tatttgtttc 540 taaaattact tgttttccag tttttatttt ttttagagaa aattcttaag tctcagtttc 600 c 601 125 601 DNA Homo sapiens 125 ttcagaaata acttatcagt tatttctgta agcttcttgc ttacctggat acctgacagg 60 tgagatggct gtagcagaca ctggcagttc cctgcccaca cacctgtccc tgtccacagc 120 tgcacaaggc agctctgtgt gcaattgcca gcatctgctc ctctgttctc agggaatctt 180 tgttagaaaa atgctgccat atttgtttct cacctattag tcttgtctcc cagtcaagag 240 aataaattta tgcaagcaga gattgtactt tacagtattt tgtctttgag cttggcatta 300 kgttgcattt gtaaaaatgt ggcatggctt cctcatcccc caataggaac tttgccagcc 360 cttttgttct catggaactt ccttttttga aaagagcacc aaaggagtaa aaatactgtg 420 gagggagcaa ccctcctttg ccatatgctc tcattgggag acatgtggag cagtctgaag 480 tcatttaggc cactctctgg gagagcacat cctatgatgt tctcccagcc tagccccttc 540 cactgtgctc aagtccaagc tgaccagctt tctgaccaca gtgtaaacaa agatgattgt 600 c 601 126 494 DNA Homo sapiens 126 ctgtgtgcaa ttgccagcat ctgctcctct gttctcaggg aatctttgtt agaaaaatgc 60 tgccatattt gtttctcacc tattagtctt gtctcccagt caagagaata aatttatgca 120 agcagagatt gtactttaca gtattttgtc tttgagcttg gcattaggtt gcatttgtaa 180 aaatgtggca tggcttcctc atcccccaat aggaactttg ccagcccttt tgttctcatg 240 gaacttcctt ttttgaaaag agcaccaaag gagtaaaaat actgtggagg gagcaaccct 300 yctttgccat atgctctcat tgggagacat gtggagcagt ctgaagtcat ttaggccact 360 ctctgggaga gcacatccta tgatgttctc ccagcctagc cccttccact gtgctcaagt 420 ccaagctgac cagctttctg accacagtgt aaacaaagat gattgtcagt gggccccaga 480 atcctatacc caga 494 

That which is claimed is:
 1. An isolated nucleic acid molecule consisting of a nucleotide sequence selected from the group consisting of: (a) a nucleotide sequence that encodes a protein comprising the amino acid sequence of. SEQ ID. NO:2; (b) a nucleotide sequence consisting of the nucleic acid sequence of SEQ ID No: 1; (c) a nucleotide sequence consisting of the nucleic acid sequence of SEQ ID No: 3; and (d) a nucleotide sequence that is completely complementary to a nucleotide sequence of (a)-(c).
 2. A nucleic acid vector comprising a nucleic acid molecule of claim
 1. 3. A host cell containing the vector of claim
 2. 4. A process for producing a polypeptide comprising culturing the host cell of claim 3 under conditions sufficient for the production of said polypeptide, and recovering the peptide from the host cell culture.
 5. An isolated polynucleotide consisting of a nucleotide sequence set forth in SEQ ID. NO: 1 of claim
 1. 6. An isolated polynucleotide consisting of a nucleotide sequence set forth in SEQ ID. NO:3 of claim
 1. 7. A vector according to claim 2, wherein said vector is selected from the group consisting of a plasmid, virus, and bacteriophage.
 8. A vector according to claim 2, wherein said isolated nucleic acid molecule is inserted into said vector in proper orientation and correct reading frame such that the protein of SEQ ID NO:2 may be expressed by a cell transformed with said vector.
 9. A vector according to claim 8, wherein said isolated nucleic acid molecule is operatively linked to a promoter sequence.
 10. An isolated nucleic acid molecule encoding a peptide, said nucleic acid molecule sharing at least 80 percent homology with a nucleic acid molecule shown in SEQ ID NOS: or 3 of claim
 1. 11. A nucleic acid molecule according to claim 10 that shares at least 90 percent homology with a nucleic acid molecule shown in SEQ ID NOS: 1 or
 3. 12. An isolated peptide consisting of an amino acid sequence selected from the group consisting of (a) an amino acid sequence shown in SEQ ID. NO:2; (b) an amino acid sequence of an allelic variant of an amino acid sequence shown in SEQ ID. NO:2, wherein said allelic variant is encoded by a nucleic acid molecule that hybridizes under stringent conditions to the opposite strand of a nucleic acid molecule shown in SEQ ID NOS:1 or 3; (c) an amino acid sequence of an ortholog of an amino, acid sequence shown in SEQ ID. NO:2, wherein said ortholog is encoded by a nucleic acid molecule that hybridizes under stringent conditions to the opposite strand of a nucleic acid molecule shown in SEQ ID NOS 1 or 3; and (d) a fragment of an amino acid sequence shown in SEQ ID. NO:2, wherein said fragment comprises at least 10 contiguous amino acids.
 13. An isolated peptide comprising an amino acid sequence selected from the group, consisting of: (a) an amino acid sequence shown in SEQ. ID. NO:2; (b) an amino acid sequence of an allelic variant of an amino acid sequence shown in SEQ ID NO:2, wherein said allelic variant is encoded by a nucleic acid molecule that hybridizes under stringent conditions to the opposite strand of a nucleic acid molecule shown in SEQ ID. NOS: 1 or 3; (c) an amino acid sequence of an ortholog of an amino acid sequence shown in SEQ. ID. NO:2, wherein said ortholog is encoded by a nucleic acid molecule that hybridizes under stringent conditions to the opposite strand of a nucleic acid molecule shown in SEQ ID. NOS: t or 3; and, (d) a fragment of an amino acid sequence shown in SEQ ID. NO:2, wherein said fragment comprises at least 10 contiguous amino acids.
 14. An isolated human peptide having an amino acid sequence that shares at least 70 percent homology with an amino acid sequence shown in SEQ ID NO: 2 of claim
 1. 15. A peptide according to claim 14 that shares at least 90 percent homology with an amino acid sequence shown in SEQ ID NO:2 of claim
 1. 16. A method for detecting the presence of a nucleic acid molecule of claim 1 in a sample, said method comprising contacting the sample with an oligonucleotide comprising at least 20 contiguous nucleotides that hybridizes to said nucleic acid molecule under stringent conditions, wherein the stringent condition is hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SCC, 0.1% SDS at 50-65° C., and determining whether the oligonucleotide binds to said nucleic acid molecule in the sample. 